Signaling Pathways in Proliferation and Differentiation

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DESCRIPTION (provided by applicant): The retinoblastoma tumor suppressor gene product, pRb, regulates cell cycle progression, and this represents one of its tumor suppressor functions. pRb is also a key participant in a number of differentiation programs; however, there is no compelling genetic or in vivo evidence that pRb's role in the control of cellular differentiation contributes to its tumor suppressor function. Like Rb, the three ras proto-oncogenes regulate differentiation and proliferation. Rb and ras function together to control differentiation in the mouse. Heterozygosity for K-ras or nullizygosity for N-ras (i) rescues many of the developmental defects that characterize Rb-deficient embryos by affecting differentiation, but not proliferation and (ii) significantly enhances the degree of differentiation of pituitary adenocarcinomas arising in Rb heterozygotes, leading to their prolonged survival. Together, these observations suggest that the ability of pRb to affect differentiation is a facet of its tumor suppressor function. Rb+/- mice also develop medullary (C-cell) thyroid adenomas. By contrast, Rb N-ras heterozygotes develop metastatic C-cell carcinomas, with a fraction of these showing loss of the remaining N-ras allele. This counterintuitive observation might be rationalized by the observations that tumors of neuroendocrine origin rarely display mutations in ras and introduction of oncogenic Ras into lines derived from such tumors promotes their differentiation. Research to be conducted examines how loss of N-ras contributes to the development of large primary thyroid tumors and their associated metastases using experimental assays. The possibility that the metastatic behavior of C-cell tumors arising in Rb N-ras mutant animals might be associated with acquisition of the normal migratory and invasive behavior C-cells possess during embryo genesis will be explored. A second line of research will address the requirement for different ras isoforms in transformation. Specifically, the role of K- and N-ras in SV40 T antigen-mediated transformation of murine embryo fibroblasts will be addressed. A third line of investigation is motivated by the observation that skeletal muscle in Rb ras mutant animals continues to display evidence of ongoing proliferation, despite a rescue in differentiation. Detailed research will be focused here on the molecular mechanism by which pRb and the myogenic factor, MyoD, maintain a terminal cell cycle arrest during myogenic differentiation, with emphasis on the regulation of genes known to participate in cell cycle re-entry.