Dear Science Journalist: Welcome to San Francisco, where the American Society for Cell Biology will be celebrating the “Year of the Glowing Proteins” with the winners of the 2008 Nobel Prize in Chemistry, Martin Chalfie and Roger Y. Tsien. They will accept the Society’s E.B. Wilson Medal, the ASCB’s highest scientific honor, at 7:00 pm, Tuesday, December 16, in Room 134 of the Moscone Center. But Nobel gold and fluorescent green are only part of a dazzling scientific rainbow on display at our 48th Annual Meeting, the world’s largest annual cell biology meeting.
Media-friendly Basics of the ASCB Meeting Find your own news angle: Wherever you’re based, there’s probably scientific news from “home” at the ASCB Annual Meeting. Whether your news beat is local research, specific diseases, or world trends in bioscience, you can find out who’s presenting what through the online ASCB abstract database. Go to www.ascb.org/meetings and click on “Abstracts/ Posters” and then “Itinerary Planner.” You can search by keyword, session title, institution, and/or the scientist’s last name. From the main Annual Meeting page menu, you can download a PDF of the full program and check out symposia and minisymposia presentations. Sign up for ASCB “Working Press” credentials online or onsite: Journalists can register online through Friday, December 5, at https://www.ascb.org/ascbsec/press.cfm. This link will take you to the ASCB definition of “Working Press.” Once you’ve registered online, your press badge will be waiting at the ASCB Newsroom, Room 212, in San Francisco’s Moscone Center, starting at 8:00 am, Saturday, December 13, 2008. From then on, walk-up “Working Press” registration is available onsite in San Francisco, but all journalists must bring professional— and personal—identification to the ASCB Newsroom. Cover breaking science stories at the ASCB meeting from your desk: We can help set up interviews with scientific newsmakers at the meeting. Contact ASCB Science Writer John Fleischman by email at
[email protected] or by calling the ASCB Newsroom at (415) 978-3608, December 13–17, 2008, from 8:00 am to 6:00 pm (Pacific Time). You can join our 10:00 am press briefings on Sunday, Monday, and Tuesday via toll-free conference call. For press briefing details at the meeting, contact John Fleischman at (513) 706-0212. All “Novel & Newsworthy” news stories are embargoed against broadcast and publication until 10:00 am, Pacific time, on the day of presentation. See each Novel & Newsworthy story for details and check with the ASCB Newsroom for any embargo extensions. The 10,300 members of the ASCB welcome science journalists to cover our meeting but ask you to respect these terms. For more information: Contact John Fleischman at
[email protected], (513) 929-4635 or (513) 706-0212, or Cathy Yarbrough, ASCB Annual Meeting Media Manager, at cyarbrough@ ascb.org, (858) 243-1814. See you in San Francisco.
Sincerely,
Rex Chisholm, Chair, ASCB Public Information Committee Joan R. Goldberg, ASCB Executive Director
Cell Biology 2008
Cell Biology 2008 Published by The Public Information Committee (PIC) The American Society for Cell Biology 8120 Woodmont Avenue, Suite 750 Bethesda, MD 20814-2762 Tel: (301) 347-9300; Fax: (301) 347-9310
[email protected], www.ascb.org
Table of Contents Page 2 Highlights of the ASCB 48th Annual Meeting n The hottest stem cell on the block n Taking the fast track from basic discovery to clinical trial n Biologists? Funny? CellSlam is back for more data
Public Information Committee Rex Chisholm, Chair Simon Atkinson Kerry S. Bloom Scott D. Blystone Lynne Cassimeris Duane A. Compton Thomas T. Egelhoff Holly V. Goodson
Lynn Maquat Gregory Payne Laura J. Robles Kenna Mills Shaw Kip Sluder Margaret A. Titus Katherine L. Wilson
Page 3 The Year of the Glowing Proteins Fresh from Stockholm, Nobel laureates Chalfie and Tsien accept the ASCB’s E.B. Wilson Medal Page 4 Our “Novel & Newsworthy” Top Picks for 2008 Page 5 In fruit flies, circadian rhythm controls innate immunity, rising at night and falling by day Mimi Shirasu-Hiza, Stanford University
PIC Associates Sheryl Denker Lena Diaw Kaede Gomi Lee Ligon Kathleen G. Morgan
Runa Musib James A. Olzmann Deepti Pradhan Eric Sawey Mhairi Skinner
Page 6 Blocking a molecular pathway stops deadly pancreatic cancer in its tracks Amy Tang, Mayo Clinic College of Medicine Page 7 A single muscle stem cell implanted in irradiated mouse muscle tissue proliferated, giving rise to more self-renewing stem cells Alessandra Sacco, Stanford University
Cell Biology 2008, Peer Screening Panels Simon Atkinson Scott D. Blystone Lynne Cassimeris Rex L. Chisholm Duane A. Compton Sheryl Denker Lena Diaw Thomas T. Egelhoff Kaede Gomi Holly V. Goodson Lee Ligon
Lynn Maquat Kathleen G. Morgan Runa Musib James A. Olzmann Deepti Pradhan Laura J. Robles Eric Sawey Kenna Mills Shaw Mhairi Skinner Margaret A. Titus Katherine L. Wilson
Page 8 Throwing a “photoswitch” on cancer cells lights up the microenvironment and shows how tumor cells are guided toward a blood vessel Bojana Gligorijevic, Albert Einstein College of Medicine Page 9 Crunching microarray profiles and protein pathways sorts out cancers by the numbers Trey Ideker & Han-Yu Chuang, University of California, San Diego
Cell Biology 2008, PIC Editors Simon Atkinson Rex L. Chisholm Lynn Maquat
Page 10 Genital tissue no foolproof barrier to sexual transmission of human immunodeficiency virus Thomas Hope, Northwestern University Medical School
Greg Payne Margaret A. Titus
Cell Biology 2008
Page 11 Probing the evolutionary roots of ancient bacteria may open a new line of attack on the leading cause of death in cystic fibrosis: opportunistic infection Lars Dietrich, Massachusetts Institute of Technology
John Fleischman, Editor and Writer Gabe Waggoner, Copy Editor Thea Clarke, Proofreader Cathy Yarbrough, Annual Meeting Media Mgr. Nancy Simons, Designer
Page 12 Yeast yield secrets of old age: Eat less and process lipids well when young Vladimir Titorenko, Concordia University, Montreal
For the American Society for Cell Biology Joan R. Goldberg, Executive Director
Media contacts:
Page 13 Seeing the unseen with super-resolution fluorescence microscopy Bo Huang, Harvard University
John Fleischman, ASCB Science Writer (513) 929-4635; (513) 706-0212 (cell)
[email protected] Cathy Yarbrough ASCB Annual Meeting Media Manager (858) 243-1814;
[email protected]
Page 14 Researchers may have found a new way to slam the brakes on deadly ovarian cancer Tulsiram Prathapam, University of California, Berkeley
Kevin Wilson ASCB Director of Public Policy (301) 347-9300;
[email protected]
Page 15 The primary cilium serves as a “cellular GPS” in wound repair and beyond Soren Tvorup Christensen, University of Copenhagen
At the meeting—December 13–17, 2008 ASCB Newsroom, Room 212 Moscone Center 747 Howard Street, San Francisco, CA 94103 (415) 978-3608 (Pacific Time) Fax: (888) 405-2221
Page 16 A pocket guide to the 2008 ASCB Annual Meeting Cover credits: Micrographs employing colored fluorescent proteins courtesy of Molecular Biology of the Cell (MBC): HeLa cells in metaphase by Jim Wong, Stanford University (MBC, March 2006), and collapsed time-lapse images of EB1-GFP foci by Jack Rosa, University of Massachusetts Medical Center (MBC, June 2008).
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Highlights of the ASCB 48th Annual Meeting The hottest stem cell on the block: iPS one year later
Taking the fast track from basic discovery to a clinical trial for “untreatable” children
The induced pluripotent stem (iPS) cell burst on the public scene last year with the demonstration by Shinya Yamanaka of Kyoto University that differentiated mouse cells could be reprogrammed genetically into pluripotent stem cells, able to create any tissue in the body. Suddenly the iPS cell was being hailed as a scientific, ethical, and even political breakthrough for stem cell research. A year later, Yamanaka will join other prominent ASCB stem cell researchers at the 48th Annual Meeting for a “Working Group” panel to assess the scientific reality and promise of iPS cells. Other panelists include Fred Gage of the Salk Institute; Larry Goldstein of the University of California, San Diego, School of Medicine; and Helen Blau of Stanford University School of Medicine.
This is an extraordinary story of basic cell research and a rare disease called Hutchinson-Gilford Progeria Syndrome (HGPS). Progeria, as it’s more commonly called, has been described as out of control, rapid aging in children. And yet a possible treatment for this “untreatable” disorder has suddenly emerged from basic cell biology, the Human Genome Project, and a new use for a “failed” cancer drug. The progeria bench-to-bedside story has unfolded with breathtaking speed; it has taken only five years from the discovery of the progeria gene to a clinical trial of an orphaned cancer drug as a potential progeria therapy. Moreover, researchers have new evidence that this treatment for HGPS kids opens new approaches to controlling the effects of “normal” aging, particularly in cardiovascular disease. Hear this scientific and human story first-hand from Robert D. Goldman, ASCB President and a pioneer in basic research into progeria; Francis Collins, former Director of the National Human Genome Research Institute; Mark W. Kieran, Director of the Pediatric NeuroOncology Program, Dana-Farber Cancer Institute; and Leslie Gordon, Medical Director of the Progeria Research Foundation and parent of a child with progeria.
Working Group: Impact Of Stem Cell Research on Cell Biology Minisymposium 22, Tuesday, December 16, 3:40 pm–5:45 pm Room 308, Moscone Center
Translational Research Session: “Translating Progeria: A Bench-to-Bedside Story” Sunday, December 14, 12:15 pm–1:45 pm Room 304, Moscone Center
Cell biologists? Funny? CellSlam is back for more data Wiser heads have once more been overruled as the ASCB’s highly improbable, stand-up science slam returns for its third outing, “CellSlam 2008: The SF Shoutout,” on Tuesday, December 16. The strangest show in science, CellSlam attempts to refute all previous data that cell biologists can’t be funny and that they can’t communicate science to the general public. With a distinguished judging panel of scientists and science journalists watching in disbelief, each CellSlam contestant will get three minutes, a mike, and no AV to make a bioscience issue, concept, or discovery come alive before a live audience. Last year’s CellSlam in Washington, DC, attracted a judging panel of distinguished science journalists from the New York Times, Washington Post, Science, and Nature who watched open-mouthed as ASCB cell biologists rapped, sang, recited poetry, and waved cheerleading pompoms. The journalists’ verdict? CellSlam has to be seen to be believed. With no prizes other than bragging rights, CellSlam 2008 is an official Fun Event of the ASCB Annual Meeting. “CellSlam 2008: The SF Shoutout” Tuesday, December 16, 8:00 pm, Room 130, Moscone Center
The year of the glowing proteins Fresh from Stockholm, “GFP” Nobel laureates Martin Chalfie and Roger Y. Tsien accept ASCB’s E.B. Wilson Medal at San Francisco meeting It is hard to imagine cell biology today without GFP, the green fluorescent protein that triggered an explosion in live cell imaging and a revolution in molecular biology. GFP and its multicolored descendents are as essential to modern cell biology as microscopes, model organisms, or glassware. This year, the Nobel Prize in Chemistry was awarded to two longtime ASCB members who pioneered the development of these genetically insertable fluorescent “tags,” Martin Chalfie of Columbia University and Roger Y. Tsien of the University of California, San Diego. Along with Osamu Shimomura of the Marine Biology Laboratory (MBL), Chalfie and Tsien will receive their Nobel medals and a third share each of the $1.4 million prize from the King of Sweden on December 10 in Stockholm. Six days later, Chalfie and Tsien will be in San Francisco to receive the E.B. Wilson Medal, the ASCB’s highest scientific honor, at the Society’s 48th Annual Meeting. The ASCB had already selected Tsien and Chalfie last spring to receive the 2008 Wilson medal but after the Nobel was announced in October, it was unclear if the two laureates would be back in the U.S. in time. Fortunately, the ASCB was able to reschedule the Wilson medal ceremony to Tuesday, December 16, and the laureates were happy to accept the revised date. The original green fluorescent protein was discovered by Shimomura in a Pacific coast jellyfish, Aquaria victoria. Another MBL scientist, Douglas Prasher, isolated the jellyfish fluorescent gene, but it was Chalfie who first inserted the GFP gene into six individual cells in the model organism Caenorhabditis elegans. Under ultraviolet light, the labeled cells glowed bright green, making it possible for the first time to follow protein movement in a living animal. Tsien refined the original GFP and extended its color palette so that scientists could follow the interactions of differently labeled proteins within the same cell.
© ® The Nobel Foundation
Martin Chalfie
E.B. Wilson Medal and Lecture Martin Chalfie, Columbia University Roger Y. Tsien, University of California, San Diego/HHMI Tuesday, December 16, 7:00 pm Room 134, Moscone Center
Roger Y. Tsien
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It’s not easy finding the hottest news… at the world’s largest annual meeting of research biologists. ASCB members submitted 3,451 abstracts for presentation at the 2008 Annual Meeting in San Francisco. Throw in keynote speeches, lectures, and special interest groups, and it gets confusing. Fortunately, finding the breaking news and the coolest science is what “Cell Biology 2008,” our “peerscreened” press book, is all about. This year, the Public Information Committee (PIC) started with the 1,043 abstracts submitted for talks. We grouped 22 PIC members and PIC Associates into five separate screening panels. We read and we ranked, and we whittled that down to 182. Then we screened again. Here’s the result, our “2008 Novel & Newsworthy” top picks.
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Goodnight immunity In fruit flies, circadian rhythm controls innate immunity, rising at night and falling by day
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he fruit fly, Drosophila melanogaster, entered the world of science in 1900 through an open window and a forgotten bunch of grapes left in the Harvard laboratory of biologist William E. Castle. Easy to keep, feed, and breed, Drosophila has been a research pioneer ever since, unraveling the basics of genetics, embryonic development, and the biological underpinnings of behavior. Now the fruit fly steps into yet another research arena, the relationship between biological time and innate immunity. Biological time refers to circadian rhythm, the protein clock in our cells that paces us through our days and nights, setting the rest–activity cycle that tells us when to eat, sleep, and mate. Flies have their own circadian rhythm, and now Mimi Shirasu-Hiza and David Schneider at Stanford University have evidence that circadian rhythm affects (and is affected by) immunity. In previous experiments, the researchers had infected Drosophila with two different bacterial pathogens, Listeria monocytogenes and Streptococcus pneumoniae. They found that sick flies lost their circadian rhythm and that flies without circadian rhythm were highly susceptible to infection. To test whether circadian proteins regulate immunity, Shirasu-Hiza infected flies with these pathogens at different times of day or night. Circadian proteins oscillate in activity over a 24-hour cycle, acting as a molecular clock or timing mechanism. She found that flies infected at night survived better than flies infected during the day. Hoping to identify specific immune responses that oscillate with circadian rhythm, Shirasu-Hiza took a closer look at phagocytosis, an integral part of the innate immune response whereby immune cells engulf and destroy invading bacteria. Shirasu-Hiza found that in
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The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Sunday, December 14, 2008
Recruited to science by a bunch of grapes, the tiny fruit fly Drosophila revolutionized biology in the 20th century and continues to do so in the 21st. Edith M. Wallace painted this watercolor in 1919 for fruit fly geneticist Thomas Hunt Morgan. Morgan and his Drosophila won the Nobel Prize in 1933. Illustration courtesy of the Carnegie Institution of Washington.
flies, phagocytic activity oscillates with circadian rhythm—low during the day and peaking at night. She also found that some circadian mutants have low phagocytic activity. “These results suggest that immunity is stronger at night, consistent with the hypothesis that circadian proteins upregulate restorative functions such as specific immune responses during sleep, when animals are not engaged in metabolically costly activities,” she says. The implications go beyond flies, Shirasu-Hiza adds. In people, immune responses such as phagocytosis are not only involved in clearing bacterial infection but also are implicated in a growing number of human diseases, including cancer and neurodegenerative disorders. By elucidating the circadian connection to immunity, the fruit fly may perform yet another great service to science.
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Mimi Shirasu-Hiza Stanford University 299 Campus Dr. Fairchild D333 MC 5124 Stanford, CA 94305-5101 (650) 380-5524
[email protected]
Author presents
Sunday, December 14 5:25 pm Minisymposium #1 Program #15 Cell Biology of the Immune System Room 301, Moscone Center
Circadian Rhythm and Immunity in Drosophila: A Model for Neuroimmune Communication M. Shirasu-Hiza, D. Schneider Microbiology and Immunology, Stanford University, Stanford, CA
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The most lethal cancer Blocking a molecular pathway stops deadly pancreatic cancer in its tracks News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Sunday, December 14, 2008
Contact
Amy Tang Mayo Clinic College of Medicine 200 1st St. SW Medical Sciences Bldg. MS2-85 Rochester, MN 55905-0001 (507) 538-0313
[email protected]
Author presents
Sunday, December 14 1:30 pm Cancer I: Signaling Program #713 Board #B678 Halls A-C, Moscone Center
Inhibition of K-RAS–mediated Tumorigenesis and Metastasis by Blocking SIAH E3 Ligase– dependent Proteolysis in Pancreatic Cancer
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t’s a target with a funny name— “seven-in-absentia homolog”—but if results from the laboratory of Amy Tang at the Mayo Clinic College of Medicine in Minnesota pan out, new drugs and new hope could emerge for patients with pancreatic cancer. Until now, they have had little of either. Pancreatic cancer is the most lethal form of human cancer known; the median survival time of pancreatic cancer patients is only six months, and the mortality rate is 95%. Tang and her colleagues believe that they have found a new therapeutic target for pancreatic cancer in the proteins produced by the human gene SIAH (seven-in-absentia homolog). That name in turn is derived from plain old “seven in absentia,” or SINA, the whimsical name given to the gene when first discovered in the famous fruit fly, Drosophila melanogaster. In flies, SINA produces a family of RING domain E3 ubiquitin ligases. In all creatures, ubiquitin ligases turn cell pathways on or off by degrading proteins. In humans, the SIAH ubiquitin ligases sit smack in the middle of the molecular pathway that leads to pancreatic cancer, says Tang. The key protein in the pathway regulating cell growth is K-RAS. When K-RAS becomes hyperactivated, it sets
off a major signaling pathway that drives aggressive cellular transformation, oncogenesis, and metastasis in pancreatic cancers. Virtually all patients with pancreatic adenocarcinomas have mutations that hyperactivate K-RAS. The Tang lab found that SIAH ubiquitin ligases were specifically and markedly upregulated in pancreatic cancers. The increased SIAH expression seemed to correlate with increased grades and aggressiveness of pancreatic cancer. Moreover, SIAH is normally required for mammalian K-RAS signal transduction. By inhibiting SIAH function, the researchers abolished both tumorigenesis and metastasis of human pancreatic cancer cells growing in special mice (called nude because they are hairless) that have immune system deficits that prevent them from rejecting foreign tissue. The SIAH protein seems to work as a checkand-balance mechanism in the K-RAS pathway by chewing up and turning off proteins that regulate pancreatic cell growth, says Tang. “By attacking the SIAHbased protein degrading machinery, we block tumor formation in one of the most aggressive human cancers known.” SIAH is therefore an attractive new target for new anti-RAS and anticancer therapy in pancreatic cancer. “It is likely to move into the clinical setting for study as an interventional treatment in pancreatic cancer in human patients,” Tang believes.
In pancreatic cancer (left), the ubiquitin ligase with the funny name of “seven-inabsentia homolog” or SIAH is the most downstream component in the long RAS metabolic pathway (right) that leads to tumor formation. Blocking SIAH blocks cancer progression. AntiSIAH molecules have potential as new and effective agents against human pancreatic cancer, possibly in the near future.
R.L. Schmidt, A.H. Tang Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN C.H. Park, A.U. Ahmed, N.R. Reed, J.H. Gundelach, B.E. Knudsen, A.H. Tang Surgery, Mayo Clinic College of Medicine, Rochester, MN
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Stem cell “gold standard” A single muscle stem cell implanted in irradiated mouse muscle tissue proliferated, giving rise to more self-renewing stem cells
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wipe out the endogenous MuSC population and then implanted one luciferaseexpressing MuSC. Using luminescent imaging along with quantitative and kinetic analyses, Sacco and Blau tracked the transplanted stem cell as it rapidly proliferated and engrafted its progeny into the irradiated muscle tissue, forming new myofibers. The researchers then re-isolated the luciferase-glowing MuSCs to demonstrate that the cells’ self-renewal powers were intact. The glowing MuSC had met the gold standard. “We are thrilled with the results,” says Sacco. “It’s been known that these satellite cells are crucial for the regeneration of muscle tissue, but this is the first demonstration of self-renewal of a single cell.” Being able to isolate and then transplant skeletal MuSCs could have a broad effect in a variety of muscle-wasting diseases such as muscular dystrophy and in treating severe muscle injuries or loss of function from aging and disuse. In other experiments, the researchers transplanted between 10 and 500 luciferasetagged MuSC into mouse leg muscle. Again the cells proliferated and engrafted, forming new myofibers. Furthermore, the transplanted stem cells reached homeostasis; that is, unlike tumor cells, the transplants grew to a stable, constant level and stopped replicating. Injuring the transplanted muscles set off massive waves of muscle cell growth and repair, demonstrating that this population had rescued the lost muscle healing function.
oti-, pluri-, or multipotent stem cells are sorted out by their unique potency both to change and to remain unchanged. Only a true stem cell can renew itself over a lifetime while still churning out specialized progenitor cells. That makes the “gold standard” test for useful adult multipotent stem cells brutally simple. First you must isolate a stem cell population. Then you must transplant one stem cell into an individual lacking the function supplied by that stem cell and its differentiated descendants. The transplanted stem cell must proliferate and generate both progenitors that participate in tissue regeneration and new stem cells. Then you must recover these new stem cells from the transplant to demonstrate that selfrenewal has occurred. Alessandra Sacco and Helen Blau of Stanford University have applied this gold standard to adult muscle stem cells (MuSCs) isolated from a mixed population of satellite cells in mouse skeletal muscle. Adult MuSCs were thought to be a subset of these satellite cells, living just under the membrane that surrounds muscle fibers. They respond to muscle damage by giving rise to progenitor cells that become myoblasts, fusing into myofibers to repair muscle tissue. Using a protein marker for satellite cells, Pax7, Sacco and Blau isolated MuSCs from a line of lab mice genetically engineered to express the glowing protein luciferase. Every cell in their bodies glows, making the luciferase and Pax7expressing MuSCs easy to trace when implanted into a nonglowing mouse. The researchers used special immuneFreshly isolated skeletal MuSCs (left) tagged with green fluorescent proteins suppressed, nonglowing were transplanted into recipient mice. A month after transplant, leg muscle mice for the transplant was damaged by injection. Five days later, the fluorescent cells were found engrafted in the satellite cell position (arrow head) indicating MuSC selftest. They first irradiated renewal. Freshly isolated MuSCs from double-transgenic mice were injected a hind limb muscle to
News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Sunday, December 14, 2008
Contact
Alessandra Sacco Stanford University 269 Campus Dr. CCSR Bldg., Rm. 3200 Stanford, CA 94305-5101 (650) 736-0081
[email protected]
Author presents
Sunday, December 14 1:30 pm Stem Cells I Program #628 Board #B590 Halls A-C, Moscone Center
Self-Renewal and Expansion of Single Transplanted Muscle Stem Cells A. Sacco, R. Doyonnas, P. Kraft, H.M. Blau Microbiology and Immunology, Stanford University, Stanford, CA
into recipients (right) and imaged four weeks after transplantation.
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A small tumor is a large place Throwing a “photoswitch”on cancer cells lights up the microenvironment and shows how tumor cells are guided toward a blood vessel News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Monday, December 15, 2008
Contact
Bojana Gligorijevic Albert Einstein College of Medicine 1300 Morris Park Ave. Forchheimer 628 Bronx, NY 10461-1975 (718) 678-1130
[email protected]
Author presents
Monday, December 15 5:25 pm Minisymposium #13 Program #785 Imaging and Biosensors Room 302, Moscone Center
Determining Spatial and Temporal Limits of the Tumor Intravasation Microenvironment In Vivo
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mall tumors are like minor surgery: If it’s your surgery, it’s not minor. If it’s your tumor, it’s not small. But increasingly, biologists are discovering that even a small tumor can be a large place and that a cell’s location—its microenvironment—within a tumor can decide its fate. That’s because cells are always signaling to each other. Figuring out what individual tumor cells are saying could tell researchers how to break up the cancer conversation. But tracking single cells or even small groups in a tumor is difficult. Using the power of genetically inserted fluorescent marker proteins, scientists have had some success in tissue culture, but the tumor microenvironment in living creatures is much more complex—frustratingly so, say researchers at the Gruss Lipper Biophotonics Center at the Albert Einstein College of Medicine in New York. They now report a breakthrough technique that allows them to watch individually labeled tumor cells move about in real time and in a real mouse. Bojana Gligorijevic, Dmitry Kedrin, and Jacco van Rheenen, in the labs of Jeff Segall and John Condeelis, have been able to watch a tumor get organized over time through a special glass “window” inserted into the tumor in a mammary gland. The researchers marked cancer
cells in the tumor with a green fluorescent protein and then bathed two small groups of cells in a blue laser, permanently “photoswitching” the green fluorescence to red. Through the window, the researchers followed the red-switched cancer cells as they grew and moved about in reaction to their microenvironment. Gligorijevic and her colleagues are interested in intravasation, the deadly process by which certain tumor cells invade the surrounding basal membrane and tap into blood vessels. In their experiment, the two red-switched cell populations were only five cell diameters apart in the tumor, but location made all the difference, Gligorijevic reports. One group was near a flowing blood vessel; the other, farther “inland” in the tumor. Twenty-four hours after the red markers were switched on, the team could see the cells near the vessel moving toward the blood supply. The number of marked cells decreased as they were launched into the blood vessel. Meanwhile, the inland cancer population had moved little but increased in number. Gligorijevic says that they plan to focus on the differences between the two microenvironments, looking for the critical interactions that drive intravasation in one part of the tumor and not in the other. “Using this approach, we can now link the behavior of individual tumor cells to the type of microenvironment within the tumor, a classification which will help us in developing and testing microenvironment-specific drugs,” Gligorijevic explains.
B. Gligorijevic, D. Kedrin, J. Wyckoff, J. Segall, J. van Rheenen, J. Condeelis Department of Anatomy and Structural Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY B. Gligorijevic, J. Wyckoff, J. van Rheenen, J. Condeelis Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY
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Tumor cells are constantly moving, with different speeds and directions. This makes it hard to predict their future position. By changing the color of one cell from green to red, we can recognize a tumor cell after it has been moving around in the tissue for days. In these images taken inside a living animal, we can see connective collagen fibers in blue, fluorescently marked normal cells in green, and tumor cells “photoswitched” to red.
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The network prognosis Crunching microarray profiles and protein pathways sorts out cancers by the numbers
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ancer is a disease of cells, not organs, although many still cling grimly to the old vocabulary of “lung cancer” or “breast cancer.” Yet the advent of rapid microarray technology has made it possible to classify diseases on the basis of extensive gene expression patterns so that diagnosis can go beyond, say, estrogen-responsive breast cancer to a particular subtype of estrogen-responsive breast cancer with poor prognosis. But disease classification by gene expression remains a tricky business in patients. Cells taken from one tumor sample can be heterogeneous; genes switched on in cells from one part of the tumor may not be expressed elsewhere. Expression profiles compiled from a range of patients with the same type and grade of tumor can differ substantially. But instead of looking only at gene expression, what if you could take gene expression profiles from many breast cancer patients and match them up with the known networks of signaling pathways and protein complexes in human cells? Could you identify subgroups in which gene expression changes would allow you to make predictions about disease progression—sorting out, for example, metastatic from nonmetastatic breast cancers?
Using bioinformatic algorithms to crunch through mountains of data, Trey Ideker and Han-Yu Chuang at the University of California, San Diego, working with Eunjung Lee and Doheon Lee of the Korea Advanced Institute of Science and Technology in Daejeon, South Korea, did just that. They took expression profiles from large cohorts of women with metastatic or nonmetastatic breast cancers and mapped them to an extensive human protein interaction network assembled from previously published studies. Ideker and colleagues then searched for “subnetworks” in which aggregate gene expression patterns distinguished one patient group from another. These new prognostic markers represented not individual genes but rather sets of cofunctional genes. According to Ideker, the subnetworks predicted the risk of metastasis more accurately than previous approaches based on gene expression alone. They also included many genes that genetic studies had associated with breast cancer but that previous gene expression studies had not uncovered. Currently the researchers are extending their new integrated analysis to other cancers, including leukemia, prostate cancer, and lung cancer. They are identifying “condition-responsive” genes within signaling and transcriptional pathways that could be used to measure activation levels, another useful tool for diagnosis and prognosis.
Pathway-based cancer diagnostics: Example p53 (TP53), Myc (MYC), and Her2 (ERBB)-related protein subnetworks from the expression profiles of breast cancer patients are shown in (a-c). Each subnetwork is indicative of the cancer metastasis potential. Nodes and links represent human proteins and protein interactions, respectively. The color of each node scales with the change in expression of the corresponding gene for metastatic versus nonmetastatic cancer. The shape of each node indicates whether its gene is significantly differentially expressed (diamond) or not (circle). A blue asterisk marks known breast cancer susceptibility genes. (d) Charts the area under the curve (AUC) classification performance of our pathway markers (PAC), conventional pathway markers (Mean, Median, and PCA), and individual genes (Gene). Th e
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The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Monday, December 15, 2008
Contacts
Trey Ideker University of California, San Diego 9500 Gilman Dr. La Jolla, CA 92093-0412
[email protected] (858) 822-4558 Han-Yu Chuang University of California, San Diego La Jolla, CA 92093-0412
[email protected] (858) 822-4665
Authors present
Monday, December 15 12:00 Noon Bioinformatics/Biological Computing Program #1261 Board #B471 Halls A-C, Moscone Center
Network-based Diagnosis and Modelling of Cancer Development and Progression H.-Y. Chuang, T. Ideker Bioinformatics Program and Department of Bioengineering, University of California, San Diego, La Jolla, CA E. Lee, D. Lee Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
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The virus beneath the skin Genital tissue no foolproof barrier to sexual transmission of human immunodeficiency virus News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Tuesday, December 16, 2008
Contact
Thomas Hope Northwestern University Medical School Department of Cell and Molecular Biology Ward 8-140 303 E. Chicago Ave. Chicago, IL 60611-3072
[email protected] (312) 503-1360
Author presents
Tuesday, December 16 3:45 pm Minisymposium #20 Cellular Response to Infectious Agents Room 104, Moscone Center
Analysis of the Interaction of HIV with Female Genital Tract Tissue as a Model to Understand Sexual Transmission A. Trull, S. McCoombe, M. McRaven, T. Hope Northwestern University Medical School, Chicago, IL
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he rise of human immunodeficiency virus (HIV) transmission through heterosexual sex has researchers scrambling for new vaccines and microbicides to block its spread, but findings by researchers at the Northwestern University School of Medicine in Chicago challenge a widely held assumption that the normal mucosal lining of the female genital tract is an effective barrier to viral penetration. Women and female adolescents now account for 26% of all new HIV cases in the United States, according to the Centers for Disease Control and Prevention (CDC). From its most recent analysis of 2005 data, CDC estimated that there were 56,300 new HIV infections that year and traced 31% of those to high-risk heterosexual contact. Yet the actual mechanism underlying male-to-female sexual transmission of HIV is not well understood. The Northwestern researchers report that HIV penetrates the genital skin barriers of female humans and macaques, primarily by moving between skin cells to quickly reach depths in the tissue where immune target cells are located. HIV penetration was more common in the outermost superficial squamous epithelial layers where, in the process of normal turnover and shedding, skin cells are no longer tightly bound together and water can normally enter. “This is an unexpected and important result,” says Thomas Hope, “because it is generally believed that the squamous epithelium of the female genital tract is an efficient barrier to viral penetration.” By labeling individual HIV virions with photoactivated fluorescent tags,
A cross section of human ectocervical tissue, stained green to show tissue structure. Blue marks cell nuclei. The viral particles of HIV are red.
Hope and colleagues watched the virus penetrate the squamous epithelium, the outermost lining of the female genital tract. The researchers saw virus interacting in both human tissue culture derived from hysterectomies and in nonhuman tissue from rhesus macaque monkeys. In as little as four hours, the labeled virions reached 50 mm beneath the skin barrier to areas where the immune system cells that HIV typically targets are located. Until now, we have known little about how the virus penetrates epithelial barriers to find its specific immune cell targets: CD4positive T cells, macrophages, Langerhans cells, and dendritic cells. Hope says that his studies show that female genital tissue does not offer a foolproof barrier against HIV. New therapeutics or prevention strategies to block the entry of HIV through the superficial layers protecting the female genital tract are urgently needed.
R.S. Veazey Tulane University, New Orleans, LA
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From geobiology to cystic fibrosis Probing the evolutionary roots of ancient bacteria may open a new line of attack on the leading cause of death in cystic fibrosis: opportunistic infection
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he agony and the ecstasy of basic research is that wherever you begin, you never know where you’ll end up. Consider the Massachusetts Institute of Technology laboratory of geobiologist Dianne K. Newman, which focuses on how ancestral bacteria on the early earth evolved the ability to metabolize minerals. What might seem a purely academic question led Newman and postdoctoral fellow Lars Dietrich to new insights into the leading cause of death among the 30,000 Americans with cystic fibrosis (CF). The pathogenic bacterium Pseudomonas aeruginosa appears as a classic opportunistic infection, easily shrugged off by healthy people but a grave threat to those with CF. An inherited disorder, CF is caused by a defective gene that controls a chloride ion channel. The defect has a catastrophic effect on cells in the mucous glands of the lungs, liver, pancreas, and intestines. Essentially, CF suffocates its victims in sticky mucus, choking the lungs or blocking the digestive tract. Advances in treatment and disease management have extended the lives of children born with CF from grade school age in the 1950s to an average today of 36.8 years, according to the Cystic Fibrosis Foundation. There is still no cure for the genetic disorder, and what typically kills CF patients is a cascade of damaging lung infections. Pathogenic bacteria such as Staphylococcus aureus weaken the CF patient, but P. aeruginosa infection signals a dangerous turn. The pseudomonads adapt to the lungs, developing antibiotic resistance and forming large anaerobic colonies sealed under thick biofilm. In a classic symptom of pseudomonad infection, the mucus that accumulates in the lungs of CF patients turns blue–green, stained by phenazines, a class of redox-active pigments produced by P. aeruginosa. Th e
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For decades, researchers believed that phenazines were exclusively antibiotics, generated by P. aeruginosa to kill off bacterial competitors. That’s not the whole story: Phenazines are not mere redox-active weapons, Dietrich and Newman say. They now have evidence that phenazines are primarily signaling molecules that allow pseudomonads to organize themselves under anaerobic conditions into structured communities. Looking at phenazines from an evolutionary perspective, the researchers used RNA arrays to see what else the small molecules might be doing. They discovered that phenazines activate the transcription factor SoxR. The researchers set out to manipulate phenazine activity in colonies of P. aeruginosa grown in the lab. Phenazines create, it turns out, a smooth biofilm surface under which the colony can prosper in anaerobic bliss. The less phenazine available, the weaker and more wrinkled the colony surface, all of which suggests to Dietrich and Newman that the phenazine-processing machinery could become a potential target for drugs to treat P. aeruginosa infections in CF patients. Says Newman, “We have a long way to go before being able to test this idea, but the hope is that if survival in the lung is influenced by phenazine—or some other electron-shuttling molecule or molecules—tampering with phenazine trafficking might be a potential way to make antibiotics more effective.”
News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Tuesday, December 16, 2008
Contact
Lars Dietrich Massachusetts Institute of Technology 31 Ames St. Cambridge, MA 02139-1305 (617) 324-2772
[email protected]
Author presents
Tuesday, December 16 1:30 pm Bacterial Development Programs: Sensing, Sporulation, and Beyond Program #2162 Board #B630 Halls A-C, Moscone Center
Redox-Active Antibiotics Control Gene Expression and Community Behavior in Divergent Bacteria D.K. Newman, L. Dietrich Department of Biology, MIT, Cambridge, MA D.K. Newman Department of Earth and Planetary Science, MIT, Cambridge, MA D.K. Newman Howard Hughes Medical Institute, MIT, Cambridge, MA These 1- to 2-cm-wide colonies of mutant P. aeruginosa are genetically unable to make phenazines. In wild-type P. aeruginosa, the presence of phenazines makes the colonies smaller and smoother. A therapeutic agent that disrupts phenazine production in P. aeruginosa could be life saving for patients with CF.
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T.K. Teal, A. Price-Whelan Division of Biology, California Institute of Technology, Pasadena, CA
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Lipids and longevity Yeast yield secrets of old age: Eat less and process lipids well when young News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Tuesday, December 16, 2008
Contact
Vladimir Titorenko Concordia University 7141 Sherbrooke St. W. SP Bldg., Rm. 501-9 Montreal, QC, Canada H4B 1R6 (514) 848-2424, ext. 3424
[email protected]
Author presents
Tuesday, December 16 12:00 Noon Development and Aging Program #2153 Board #B621 Halls A-C, Moscone Center
A Mechanism Linking Lipid Dynamics and Longevity A. Goldberg, C. Gregg, T. BoukhViner, P. Kyryakov, S. Bourque, G. Machkalyan, H. Mashhedi, S. Milijevic, A. Hossain, S. Lo, M.A. London, J.M. Lee, V. Richard, V. Titorenko Biology Department, Concordia University, Montreal, Quebec, Canada
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fter leavening bread and brewing beer, the third most interesting use of the budding yeast Saccharomyces cerevisiae may be in laboratories studying the age-old question, what is old age? Is old age the final stage of a developmental program or merely the result of a lifelong accumulation of unrepaired cellular and molecular damage? Studying baker’s yeast as a model for the mechanism of cellular aging, Vladimir Titorenko of Concordia University in Montreal sees aging as a little of both. His recent work has documented how aging yeast cells accumulate damage over time, but they do so by following a pattern laid down earlier in life by diet and by genes that control metabolism and organelle dynamics. Titorenko calls this diet-plus-metabolic-genes pattern a “modular longevity network,” and has taken a closer look at one of its key modules—lipid metabolism. The Titorenko lab studied how calorie restriction—low-calorie diets increase life span and delay age-related disorders in many organisms—alters how fats are processed in the cell. The researchers assessed the effect of calorie restriction along with several mutations known to extend yeast life span on a variety of agerelated changes in fat metabolism and lipid transport. Titorenko reports the discovery of a mechanism closely linking lipid dynamics and longevity. In this mechanism, a calorie-rich diet suppresses the ability of
peroxisomes (organelles that neutralize toxic peroxides) to oxidize fatty acids. Fatty acids are constantly made in the endoplasmic reticulum (ER), and without peroxisome processing they end up in storage structures called lipid bodies. This accumulation of fatty acids sets off a process leading to the production of a lipid called diacylglycerol. This process has two bad consequences for the cell: (1) the buildup of fatty acids promotes necrotic cell death, which is a polite way of saying that the yeast explodes from within, scattering its contents and spreading inflammation to its neighbors, and (2) the accumulation of diacylglycerol impairs the yeast’s ability to defend against stress. To see whether this mechanism could be manipulated, the Titorenko lab developed an assay to undertake a highthroughput screen of chemical libraries for compounds that affect life span. They identified five groups of new antiaging small molecules. These chemicals significantly delayed yeast aging by altering lipid dynamics in the ER, peroxisomes, and lipid bodies or by activating stress response–related processes in mitochondria. These small molecules can be used as research tools for studying mechanisms of longevity, says Titorenko, and as possible pharmaceutical agents for age-related disorders that affect lipid metabolism such as atherosclerosis, chronic inflammation, and type 2 diabetes.
Neutral lipids in “young” yeast cells are synthesized in the ER and deposited within lipid bodies (green fluorescence). The hydrolysis of these lipids in lipid bodies of “old” yeast cells results in the formation of fatty acids. Fatty acids are then oxidized in peroxisomes. By suppressing the oxidation of fatty acids in peroxisomes, a calorie-rich diet sets off a cascade of chemical reactions that ultimately lead to the accumulation of fatty acids and a lipid called diacylglycerol. The buildup of fatty acids triggers necrotic cell death, whereas the accumulation of diacylglycerol impairs many of the yeast’s stress response-related defenses. A combined action of these two mechanisms shortens yeast life span. A low-calorie diet extends yeast longevity by preventing the accumulation of fatty acids and diacylglycerol in “old” cells.
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Resolving the blind spot Seeing the unseen with super-resolution fluorescence microscopy
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n the cellular scale, life gets interesting below 200–300 nm. That’s the length scale of most intracellular structures and the level at which the cell carries out most of its work. Unfortunately, it’s a blind spot for conventional light Fluorescent imaging can only capture a fuzzy image of a filamicroscopes. Even when using mentous cytoskeleton structure (green) and a round membrane fluorescent-tagged molecules, structure (red). STORM clearly resolves these two structures from light microscopes cannot reeach other even when they are densely packed. solve two objects closer than half the wavelength of the light because of the phenomenon called diffraction. Their images look blurry and overlap no matter how high the magnification. This resolution limit is like the fat man wearing a tall hat in the movie seat in front of you. He’s blocking the best part of the picture. Now comes a new “super-resolution” fluorescence The 3D STORM image reveals the hemispherical cage shape of microscopy technique that may clathrin-coated pits, which can be seen from the cross sections in at least get the fat man to rethe two perpendicular directions. For comparison, only a featureless move his hat. spot can be seen in the conventional fluorescence image. Developed by Bo Huang, Xiaowei Zhuang, and colleagues at Harvard University, stochassmaller than what conventional fluorestic optical reconstruction microscopy cence microscopy can achieve. Huang (STORM) is one of several higher-resoluand colleagues have now adapted STORM tion fluorescence microscopy techniques to study three-dimensional (3D) structures. invented recently that fundamentally They can now visualize a whole cell with surpass the diffraction limit. STORM can an axial resolution of 50–60 nm. Multirecord light emitted from one molecule in color imaging has been realized using the sample. Using probe molecules that photoswitchable fluorophores made of can be “photoswitched” between a viscombined pairs of various activator dyes ible and an invisible state, STORM deterand reporter dyes. Combined multicolor mines the position of every molecule of and 3D STORM images revealed detailed interest and then compiles their positions interactions between cell organelles and to define a structure. the cytoskeleton. In brain tissue, the techWith STORM, the Harvard researchnique revealed fine details of the synaptic ers laterally resolved cellular features as structure of the olfactory system. small as 20–30 nm, an order of magnitude
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News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Tuesday, December 16, 2008
Contact
Bo Huang Harvard University 12 Oxford St. #131 Cambridge, MA 02138-2902 (617) 384-9078
[email protected]
Author presents
Tuesday, December 16 1:30 pm Imaging Technology II Program #2014 Board #B478 Halls A-C, Moscone Center
Seeing the Unseen in a Cell With Super-Resolution Fluorescence Microscopy B. Huang, B. Brandenburg, X. Zhuang Howard Hughes Medical Institute, Harvard University, Cambridge, MA B. Huang, S.A. Jones, B. Brandenburg, X. Zhuang Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA M. Bates School of Engineering and Applied Sciences, Harvard University, Cambridge, MA W. Wang, X. Zhuang Department of Physics, Harvard University, Cambridge, MA G.T. Dempsey Graduate Program in Biophysics, Harvard University, Cambridge, MA 13
Exploiting a cancer’s addiction Researchers may have found a new way to slam the brakes on deadly ovarian cancer News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Wednesday, December 17, 2008
Contact
Tulsiram Prathapam University of California, Berkeley 16 Barker Hall #3204 Berkeley, CA 94806 Tel: (510) 642-7991
[email protected] tulsiram_prathapam@yahoo. com
Author presents
Wednesday, December 17 1:30 pm Oncogenes and Tumor Suppressors Program #2735 Board #B446 Halls A-C, Moscone Center
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varian cancer cells are “addicted” to a family of proteins produced by a notorious oncogene, MYC, say cell biology researchers at the University of California, Berkeley. Blocking these oncoproteins shuts down cell proliferation in the deadliest cancer of the female reproductive system. On the basis of work in cultured human ovarian cancer cells, Tulsiram Prathapam, G. Steven Martin, and colleagues believe that their success with Myc protein inhibition could open a new therapeutic approach to ovarian cancer. Until now, treatment advances for ovarian cancer have lagged substantially behind those for other gynecological cancers. For American women, ovarian cancer may not be the most common cancer of the reproductive system, but it is the most lethal. The American Cancer Society predicts that in 2008 there will be 21,650 new cases of ovarian cancer and 15,520 deaths. Compare those figures with those for cervical cancer, for which there will be roughly twice as many new cases— 40,000—but fewer than half as many deaths—7,470. The trends in mortality charted by the National Cancer Institute for 1996–2005 fell 3.4% for cervical cancer but only 0.2% in the same period for ovarian cancer.
Molecular Mechanism of MYC Oncogene Addiction in Ovarian Cancer
Real improvements in survival rates must come from a deeper knowledge of the biology of ovarian cancer, say Prathapam and Martin, who have been investigating the complicated role of the MYC oncogene and how its various protein forms drive the disease. This oncogene is amplified in 30%–60% of human ovarian tumors, usually through the presence of extra chromosomal copies of the MYC gene. These extra MYC copies overexpress a protein, c-Myc, that regulates other genes involved in cellular growth and proliferation, pushing them into cancer development. When Prathapam and colleagues used RNA interference (RNAi) on tumor cells with amplified c-Myc, they stopped the cancer cell cycle in its tracks. But when they tried the RNAi technique on tumor cells in which the MYC gene was not amplified, the cancer cells weren’t fazed. The researchers suspected that other forms of the Myc protein—L-Myc and N-Myc— were still functioning strongly enough to maintain cell proliferation. Using small interfering RNA to silence those isoforms, they shut down the nonamplified MYC tumors as well. Blocking all the Myc proteins in a culture of normal ovarian surface epithelial cells did not affect their ability to grow. “Our findings suggest that ovarian cancer cells are addicted to members of the MYC family for cell proliferation,” the researchers conclude, “and that growth of ovarian cancer may be blocked by MYC inhibition.” MYC amplified ovarian cancer cells are MYC-dependent while MYC nonamplified ovarian cancer cells are dependent on other isoforms of MYC. The block in the cell cycle observed in both situations can be rescued by inhibition of the p27Kip1 cell cycle regulator.
T. Prathapam, A. Aleshin, G. Martin Department of Molecular and Cell Biology, University of California, Berkeley, CA Y. Guan, J.W. Gray Department of Laboratory Medicine, University of California, San Francisco, CA Y. Guan, J.W. Gray Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA
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Steering aid The primary cilium serves as a “cellular GPS” in wound repair and beyond
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f cells held high school reunions, the primary cilium would be the class nerd who comes back in glory as a bioscience millionaire. Once written off as a vestigial organelle left in the evolutionary dust, the primary cilium has in the last decade risen to prominence as a vital cellular sensor at the root of everything from polycystic The primary cilium (upper left) functions as a cellular GPS to coordinate directional cell migrating. PDGF-AA is a chemo-attractant (upper right) that kidney disease to cancer signals through its receptor, PDGFRa, in the fibroblast cilium, which then to left–right anatomical orients in front of the nucleus and parallel to the migration path. Signalabnormalities. Now comes ing through the cilium causes reorganization of cytoskeletal components evidence that the primary (F-actin and microtubules, MT), leading to directional cell migration. The fluorescent image (inset in upper left) shows a migrating cell with the cilium cilium may act as a “celstained with anti-detyrosinated tubulin (glu-tub, green), the centrosome with lular GPS,” orienting cells pericentrin (Pctn, red) and the nucleus with DAPI (blue). The inset images that play a critical role in (bottom right) show that PDGFRa (red) localizes to the cilium stained with wound healing to move in anti-acetylated tubulin (tb, green). the right direction. The primary cilium uniquely carries Soren T. Christensen and colleagues a critical receptor for platelet-derived at the University of Copenhagen in Dengrowth factor alpha (PDGFR-a). When mark and the Albert Einstein College of activated by its ligand, PDGF-AA, PDGFRMedicine in the Bronx have discovered a transmits information from the cilium that the primary cilia of cultured fibroto the cell, reorganizing the cellular cytoblasts are oriented to detect a growth skeleton and causing it to move the cell factor signal critical to efficient wound in the right direction and at a faster pace. closure. When properly stimulated, the This mechanism is blocked in mutant primary cilia steer fibroblast cells toward cells with no primary cilia. “What we are the wound. Furthermore, mice with engidealing with is a physiological analogy neered defects in the formation of prito a global positioning system with a mary cilia show a reduced rate of wound coupled autopilot that coordinates air repair and have defects in wound closure. traffic or tankers on the open sea,” says “The really important discovery is Christensen. that the primary cilium detects signals, The researchers suspect that this celwhich tell the cells to engage their comlular GPS plays other roles beyond wound pass reading and move in the right direchealing. They say that it could serve as a tion to close the wound,” Christensen fail-safe device against uncontrolled cell explains. The primary cilia are solitary, movement. Without chemical stimulaantenna-like structures that protrude tion, the primary cilium would restrain through the membrane from a cencell migration, preventing the dangerous trosome at the cell surface. Primary cilia displacement of cells that is associated are found on almost every nondividing with invasive cancers and fibrosis. On the cell in the body. “In mutant cells that lack other hand, a defective primary cilium the [primary] cilium,” Christensen conmight fail to provide correct directional tinues, “cell migration is unregulated with instructions during cell differentiation. uncontrolled directional cell displaceThe researchers suggest that this could be ment during wound closure, leaving the another factor linking the primary cilium cells blindfolded to some of the signals to severe developmental disorders. that permit the cells to navigate correctly.” Th e
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News from
The American Society for Cell Biology 48th Annual Meeting San Francisco, CA December 13–17, 2008 EMBARGOED FOR RELEASE
10:00 am, U.S. Pacific Time Wednesday, December 17, 2008
Contact
Soren Tvorup Christensen University of Copenhagen Universitetsparken 13 August Krogh Building Copenhagen, Denmark, DK-2100 45 35 32 17 05
[email protected]
Author presents
Wednesday, December 17 1:30 pm Cilia and Flagella IV Program #2553 Board #B262 Halls A-C, Moscone Center
The Primary Cilium Coordinates Directional Cell Migration L. Schneider, S. Nielsen, I. Veland, S.T. Christensen Department of Biology, University of Copenhagen, Copenhagen, Denmark
M. Cammer Analytical Imaging Facility and
Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY
J. Lehman, B.K. Yoder Department of Cell Biology,
University of Alabama at Birmingham, Birmingham, AL
P. Satir Department of Anatomy and
Structural Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY
C. Stock, A. Schwab Institute of Physiology II, Munster University, Munster, Germany
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The ASCB 48th Annual Meeting December 13–17, 2008 Moscone Center, San Francisco, CA Robert D. Goldman, President
Keynote Symposium Saturday, December 13
Cell Biology in the Genomic Era—6:00 pm Francis S. Collins, National Human Genome Research Institute/NIH
Symposia Sunday, December 14
Cell Biology of the Senses—8:00 am Craig Montell, Johns Hopkins University School of Medicine Ulrich Mueller, The Scripps Research Institute Leslie B. Vosshall, The Rockefeller University Chromatin Organization and Gene Expression—10:30 am Susan M. Gasser, Friedrich Miescher Institute for Biomedical Research John T. Lis, Cornell University Tom Misteli, National Cancer Institute/NIH
Monday, December 15
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David L. Spector, Program Chair
Dynamic Nature of the Nucleoplasm Genevieve Almouzni, Centre National de la Recherche Scientifique/Institut Curie Thoru Pederson, University of Massachusetts Medical School Michael Rout, Rockefeller University John Sedat, University of California, San Francisco Impacts of Stem Cell Research on Cell Biology Helen Blau, Stanford University School of Medicine Fred H. Gage, The Salk Institute for Biological Studies Lawrence B. Goldstein, University of California, San Diego, School of Medicine/HHMI Shinya Yamanaka, Kyoto University
Minisymposia 3-D Electron Microscopy Jenny Hinshaw, National Institute of Diabetes and Digestive and Kidney Disease/NIH Gina Sosinsky, University of California, San Diego Actin and Actin-related Proteins Alexander Bershadsky, Weizmann Institute of Science Louise Cramer, University College London
Development and Regeneration—8:00 am Brigid Hogan, Duke University Medical Center Phillip Newmark, University of Illinois at Urbana-Champaign Didier Stainier, University of California, San Francisco
Actin-based Motors John A. Hammer, National Heart, Lung, and Blood Institute/ NIH Matthew J. Tyska, Vanderbilt University Medical Center
Cell Migration and Metastasis—10:30 am John Condeelis, Albert Einstein College of Medicine Anna Huttenlocher, University of Wisconsin Joan Massagué, Memorial Sloan-Kettering/HHMI
Apoptosis Sally Kornbluth, Duke University Medical Center Kodi S. Ravichandran, University of Virginia
Tuesday, December 16
Nuclear Organization and Disease—8:00 am Titia deLange, The Rockefeller University Gideon Dreyfuss, University of Pennsylvania School of Medicine/HHMI Roland Foisner, Medical University Vienna Cytoskeletal Dynamics—10:30 am Ueli Aebi, Biozentrum, University of Basel Claire Walczak, Indiana University Toshio Yanagida, Osaka University
Wednesday, December 17
Gene Regulation and Non-Coding RNAs—8:00 am Gregory J. Hannon, Cold Spring Harbor Laboratory/HHMI Edith Heard, Institut Curie Gisela Storz, National Institute of Child Health and Human Development/NIH Models for Stem Cell Biology—10:30 am Judith Kimble, University of Wisconsin-Madison Arnold Kriegstein, University of California, San Francisco Haifan Lin, Yale University School of Medicine
Working Groups Cellular Basis for Motor Neuron Degeneration Don Cleveland, Ludwig Institute for Cancer Research, University of California, San Diego Kenneth Fischbeck, National Institute of Neurological Disorders and Stroke/NIH Erika Holzbaur, University of Pennsylvania School of Medicine Livio Pellizzoni, Columbia University Medical Center
Cell Biology of the Immune System Jason Cyster, University of California, San Francisco/HHMI Michael Dustin, New York University School of Medicine Cell Biology of the Synapse Jose Esteban, Universidad Autónoma de Madrid Elly Nedivi, Massachusetts Institute of Technology Cell Polarity and Epithelial Morphogenesis Elisabeth Knust, Max Planck Institute of Molecular Cell Biology and Genetics Ian G. Macara, University of Virginia Cell–Cell Communication Timothy Springer, Harvard Medical School/Immune Disease Institute Cornelis Wiejer, University of Dundee Cellular Basis of Morphogenesis Lila Solnica-Krezel, Vanderbilt University Deborah Yelon, Skirball Institute, New York University School of Medicine Cellular Response to Infectious Agents Thomas J. Hope, Northwestern University Feinberg School of Medicine F. Gisou van der Goot, Ecole Polytechnique Fédérale de Lausanne Centrosomes and Cilia Susan Dutcher, Washington University School of Medicine Jordan Raff, The Wellcome Trust/Cancer Research UK Gurdon Institute Endo- and Exocytosis Karin Reinisch, Yale University School of Medicine Sanford M. Simon, The Rockefeller University
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Matthew D. Welch, Local Arrangements Chair Epigenetic Regulation Shiv Grewal, National Cancer Institute/NIH Barbara J. Meyer, University of California, Berkeley/HHMI Genomic Instability and Cancer Thomas Ried, National Cancer Institute/NIH Thea D. Tlsty, University of California, San Francisco Imaging and Biosensors Klaus Hahn, University of North Carolina at Chapel Hill Kai Johnsson, Ecole Polytechnique Fédérale de Lausanne Impact of Protein Modifications on Cell Biology Ron T. Hay, University of Dundee Deborah Morrison, National Cancer Institute–Frederick Information Technology for Cell Biology Steven J. Altschuler, University of Texas Southwestern Medical Center at Dallas Walter Fontana, Harvard Medical School Interactions with the Cytoskeleton Mary Beckerle, University of Utah/Huntsman Cancer Institute Holly V. Goodson, University of Notre Dame Intermediate Filaments and Nuclear Lamins Yosef Gruenbaum, The Hebrew University of Jerusalem Jonathan Jones, Northwestern University Medical School Lipid Dynamics Ken Jacobson, University of North Carolina at Chapel Hill Ivan Robert Nabi, University of British Columbia Membrane Heterogeneity and Trafficking Greg Odorizzi, University of Colorado Jennifer Stow, University of Queensland Microtubule-based Motors Kristen Verhey, University of Michigan Medical School Isabelle Vernos, Centre for Genomic Regulation, Pompeu Fabra University Mitosis and Meiosis Alexey Khodjakov, Wadsworth Center Christiane Wiese, University of Wisconsin–Madison Non-Coding RNAs Antonio J. Giraldez, Yale University Amy E. Pasquinelli, University of California, San Diego The Nuclear Envelope and Nuclear Pore Complex Martin Hetzer, The Salk Institute for Biological Studies Iris Meier, Ohio State University Organelle Biogenesis and Turnover Daniel Klionsky, University of Michigan Jodi Nunnari, University of California, Davis Signaling from the Extracellular Matrix Mina Bissell, Lawrence Berkeley National Laboratory Bernhard Wehrle-Haller, Centre Medical Universitaire University of Geneva, Switzerland Single Molecule Studies Siegfried Musser, Texas A&M Health Science Center James Spudich, Stanford University School of Medicine Stress Responses Jason Brickner, Northwestern University Randal Kaufman, University of Michigan Medical School/ HHMI
Gold standard stem cells Seeing the unseen with super resolution Lipids and longevity: new tips from old yeast Exploiting a cancer’s addiction From geobiology to new insights in cystic fibrosis Throwing the photoswitch on tumor cells Primary cilium as cellular GPS system All this and more at:
The 48th Annual Meeting of The American Society for Cell Biology December 13–17, 2008 | San Francisco, CA News media contact:
[email protected]
8120 Woodmont Avenue Suite 750 Bethesda, MD 20814-2762 www.ascb.org
