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Marie Classon, PhD Assistant Professor of Medicine Harvard Medical School
Assistant Geneticist Center for Cancer Research
The retinoblastoma (Rb) tumor suppressor gene and alterations in several cell cycle regulatory genes that encode proteins that participate in the regulation of pRB function are commonly observed in a broad spectrum of tumor types (p16, cyclin D and cdk4), suggesting that deregulation of this pathway is an important step in cancer development. However, different tumors exhibit selective alterations of the pathway, whether by inactivation of the cyclin-dependent kinase (cdk) inhibitor p16, increased expression of cyclin D1, mutation of cdk4 or by direct mutational inactivation of the Rb gene. We are interested in why different tumors preferentially select for mutations in one component over the other.
Initial experiments in established fibroblast cell lines from mouse strains containing inactivating mutations of pRB, p107 and/or p130 showed a striking differential sensitivity to the transforming actions of the Ras oncogene. Surprisingly, the tumor suppressor pRB was required for the transforming effect of the Ras oncogene in these cells. Human tumor cell lines harboring an activated Ras pathway often show loss of p16 expression, resulting in increased phosphorylation of RB, thought to inactivate the protein. In sharp contrats to this notion, our studies show that phosphorylated RB plays an important role in maintaining the proliferative status of these cells. This observation provides an explanation for the very high expression of RB seen in the approximately 30% of human cancers that harbor gain-of-function mutations in Ras. In addition, our experiments have suggested a novel tumor suppressive role for the Rb-related gene p107 in tumor cells harboring an activated Ras allelle. Together, these findings highlight the context dependent nature of tumor suppressor and oncogene function in human tumors. In addition, they suggest that in the context of an activated Ras pathway the Rb-relative, p107, rather than pRB, acts as a tumor suppressor and we are actively investigating the differential functions of these two related proteins in tumor cell proliferation.
Further studies in the laboratory involve an analysis of the interplay between the components of the RB pathway in the “struggle“ to achieve a balance that ultimately favors survival and proliferation of tumor cells. As a complement to these studies, we have modeled acquired resistance to drugs targeting the oncogenic Ras pathway in colorectal tumor cells as well as other tumor cell lines (in collaboration with Drs. Settleman, Sharma and Zou). These studies represent another scenario in which cancer cells adapt to a new environment and the balance between life and death requires alterations. Interestingly, the ability of tumor cells to survive in the presence of Ras pathway inhibitory drugs is reversible over time following drug withdrawal, and we are in the process of analyzing the molecular events underlying the initial resistance as well as the reversibility of this process. Importantly, an increased understanding of the adaptations that occur in tumor cells in response to genetic alterations or to oncogene inhibitory drugs will hopefully advance the treatment of cancer in the future.
Marie Classon, PhD Principal InvestigatorGroup Members
Postdoctoral Position (1)
A postdoctoral position is available to investigate context dependent functions of the retinoblastoma proteins (pRB, p107 and p130) in tumorogenesis. Our research is aimed at understanding the complex roles of the retinoblastoma protein family in tumorogenesis. We are currently using biochemical and cell biological approaches to study the context dependent roles of this family in the process of transformation. Our laboratory has previously established cells from mouse embryos deficient in the pRB family of proteins and our studies of these cells have revealed both overlapping and opposing biological functions for these closely related proteins. Specifically, this family of proteins seems to have overlapping functions in cell cycle control whereas they have opposite functions in the context of some differentiation processes. More recently, we have also found that pRB and p107 have opposing functions in Ras-mediated oncogenic transformation. Despite the frequent involvement of Ras activation and disruption of the RB pathway in a variety of human cancers, the vast majority of tumors do not exhibit both Ras activation and disruption of the Rb gene. Taken together, our findings indicate that pRB, is a necessary downstream mediator of Ras transformation, and in the context of an activated Ras pathway p107, rather than pRB, acts as a tumor suppressor.
Interested, motivated and enthusiastic applicants should have a PhD and/or MD degree, with experience in Molecular Bilogy, Biochemistry, Cell Biology or related fields. Please send a CV with past research experience and contact information of three references to:
Marie Classon, PhD Massachusetts General Hospital Cancer Center Bldg 149, 13th Street, Rm 7330 Charlestown, MA 02129 USA 1-617-726-7800 (tel) 1-617-726-7808 (fax) E-mail: email@example.com
View a list of publications by researchers at the Classon Laboratory
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