Researcher Profile
David S. Pellman, MD
Margaret M. Dyson Professor of Pediatric Oncology; Professor of Cell Biology, Harvard Medical School
Center/Program
Department
Area of Research
Cell Division and Genome Stability
Contact Information
David S. Pellman, MDDana-Farber Cancer Institute
44 Binney Street
Mayer 621A
Boston, MA 02115
Office phone: (617) 632-4918
Fax: (617) 632-6845
E-mail: david_pellman@dfci.harvard.edu
Preferred contact method: e-mail
Research
Our laboratory works on cell biology topics in two areas: cytoskeletal dynamics and the control of genome stability. Our approaches include genetics, functional genomics, biochemistry and live cell imaging. Ongoing projects use both yeast and animal cell systems.
Our work on cytoskeletal dynamics has focused on asymmetric cell division: how the mitotic spindle senses polarity cues at the cell cortex, and how the actin and microtubule cytoskeletal systems are integrated to correctly position mitotic spindles. Using biochemical and imaging approaches, we study how these protein complexes generate coordinated movement. Our group recently found that the positioning of mitotic spindles requires a novel actin assembly system mediated by formin proteins. Formins nucleate the assembly of actin filaments, which is linear - unlike the branched filaments assembled by the other known actin nucleator, the Arp2/3 complex. Formins are regulated by Rho-type GTPases. This suggests a simple model of how actin structures are formed in cells: different nucleators initiate differently shaped "building blocks" that are assembled into different structures. Our work in this area is assisted by a crystal structure of the formin actin nucleation domain. Related projects in the laboratory address: (1) the molecular mechanism of formins in living cells, (2) the mechanisms to control formin activity in cells, and (3) the cell cycle control of Rho-GTPases.
A second area in the laboratory addresses mitotic mechanisms promoting genome stability and preventing cancer. Using a mouse mammary epithelial transplant system, we recently found that inhibiting cytokinesis and generating tetraploid cells promotes tumorigenesis - the first direct test of an almost 100-year-old hypothesis. One mechanism by which tetraploid cells may promote tumorigenesis is by chaotic mitoses induced by extra centrosomes, which are a common feature of cancer cells. Cells have an adaptive mechanism to organize extra centrosomes to prevent chaotic mitoses; genome-wide siRNA screens are in progress to define these mechanisms.
In addition, we recently found that loss of certain genes results in a genetic phenomenon we call ploidy-specific lethality: the genes are not essential in cells with a normal complement of chromosomes but become essential when ploidy is increased. The ploidy-specific requirement for certain gene products could have implications for a wide variety of biological processes and may provide a new strategy to identify targets for drug development. Using functional genomic approaches in yeast and animal cells, we are now characterizing how the mechanism of mitosis is altered when ploidy is increased.
Recent Awards
- Stohlman Scholar, Leukemia and Lymphoma Society, 2005
- American Society for Clinical Investigation, 2001
- BASF Bioresearch Award, DFCI, 2001
- Scholar Award, Leukemia & Lymphoma Society, 2000
- Graduate Student Mentoring Award, Harvard Medical School, 1999
- Kimmel Scholar Award, 1998
- Damon Runyon Scholar Award, 1997
Biography
Dr. Pellman received his MD in 1986 from the University of Chicago, Pritzker School of Medicine, and did postgraduate training in pediatrics and pediatric hematology-oncology at DFCI and Children's Hospital, Boston. He was a postdoctoral fellow at the Whitehead Institute for Biomedical Research at Massachusetts Institute of Technology. In 1995, he joined DFCI, and is currently the Ted Williams senior investigator in the Department of Pediatric Oncology.
Select Publications
- Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005;437:1043-7.
- Carvalho P, Gupta M, Pellman D. Cell cycle control of kinesin-mediated transport of Bik1 (CLIP-170) regulates microtubule stability and dynein activation. Dev Cell 2004;6:815-29.
- Molk JN, Schuyler SC, Liu JY, Evans JG, Salmon ED, Pellman D, Bloom K. The differential roles of budding yeast Tem1p, Cdc15p, and Bub2p protein dynamics in mitotic exit. Mol Biol Cell 2004;15:1519-32.
- Mosley JB, Sagot I, Manning AL, Xu Y, Eck MJ, Pellman D, Goode BL. A conserved mechanism for Bni1- and mDia-induced actin assembly and dual regulation of Bni1 by Bud6 and profilin. Mol Biol Cell 2004;15:896-907.
- Storchova Z, Pellman D. Polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 2004;5:45-54.
- Xu Y, Moseley JB, Sagot I, Poy F, Pellman D, Goode BL, Eck M. Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture.
Cell 2004;116:711-23. - Carvalho P, Tirnauer J, Pellman D. Surfing on microtubule ends. Trends Cell Biol 2003;13:229-37.
- Chestukin A, Pfeffer C, Milligan S, DeCaprio JA, Pellman D. Processing, localization, and requirement of human separase for normal anaphase progression. Proc Natl Acad Sci U S A 2003;100:4574-9.
- Schuyler SC, Liu JY, Pellman D. The molecular function of Ase1p: evidence for a MAP-dependent midizone-specific spindle matrix. J Cell Biol 2003;160:517-28.
- Sheeman B, Carvalho P, Sagot I, Geiser J, Kho D, Hoyt MA, Pellman D. Determinants of S. cerevisiae dynein microtubule plus end localization and activation: implications for the mechanism of spindle positioning. Curr Biol 2003;13:364-72.
