BBS Faculty Member - Peter Sicinski

Peter Sicinski

Department of Genetics

Dana Farber Cancer Institute
Dept. of Cancer Biology, Smith Bldg., Rm. 922A
450 Brookline Ave.
Boston, MA 02215
Tel: 617-632-5005
Fax: 617-632-5006
Email: peter_sicinski@dfci.harvard.edu
Lab Members: 8 postdoctoral fellows, 1 graduate student



Our laboratory studies the role of cell cycle machinery in normal cell proliferation and in oncogenesis using mouse genetic, genomic, proteomic and systems biology approaches.

Cyclins and their catalytic partners, cyclin-dependent kinases (CDKs) are members of the core cell cycle machinery. This machinery has been conserved from yeast to humans, and it drives cell division. Consistent with their growth-promoting roles, overexpression of cyclins is seen in many human cancers. For example, cyclin D1 gene is amplified, and the protein overexpressed in the majority of human breast cancers.

In order to study the molecular function of particular cyclins in development and in cancer, we generated knockout mouse strains lacking individual cyclins, “knock-in” strains that cripple specific molecular functions of cyclins or substitute one cyclin with another, mice combining different epistatic mutations (loss of cyclin D1 and p27Kip1). These studies allowed us to decipher the function of particular cyclins in development. We also started to analyze the function of cell cycle proteins in neoplasia. Together with Dr. Hinds' laboratory (Tufts University) we found that changing a single nucleotide in the mouse genome (within the cyclin D1 gene) renders mice resistant to breast cancers. We also demonstrated that mice lacking cyclin D1, or mice lacking catalytic partner of cyclin D1, CDK4, were completely resistant to breast cancers triggered by a particular oncogenic event (overexpression of ErbB2 oncoprotein). We went on to show that the ErbB2?cyclin D1 pathway operates in a subset of human cancers. These findings led to clinical trials in which patients with ErbB2 overexpression are treated with CDK inhibitors.

We are extending this work in several directions. We are generating novel knockout mouse strains. We are combining the emerging genomic and proteomic technologies and with systems biology computational approaches to understand the function of the core cell cycle machinery in mouse development and in neoplasia. Moreover, we are extending these genomic and proteomic screens to human cancer cells.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Jirawatnotai S, Hu Y, Michowski W, Elias JE, Becks L, Bienvenu F, Zagozdzon A, Goswami T, Wang YE, Clark AB, Kunkel TA, van Harn T, Xia B, Correll M, Quackenbush J, Livingston DM, Gygi SP, Sicinski P. A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 474, 230-4 (2011).

Bienvenu F, Jirawatnotai S, Elias JE, Meyer CA, Mizeracka K, Marson A, Frampton GM, Cole MF, Odom DT, Odajima J, Geng Y, Zagozdzon A, Jecrois M, Young RA, Liu XS, Cepko CL, Gygi SP, Sicinski P. Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 463, 374-8 (2010).

Kalaszczynska I, Geng Y, Iino T, Mizuno S, Choi Y, Silver DP, Wolgemuth DJ, Akashi K, Sicinski P. Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonal stem cells. Cell 138, 352-65 (2009).

Geng Y, Lee YM, Welcker M, Swanger J, Zagozdzon A, Winer JD, Roberts JM, Kaldis P, Clurman BE, Sicinski P. Kinase-independent function of cyclin E. Mol. Cell 25, 127-39 (2007).

Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O, Sicinski P. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9, 23-32 (2006).



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