A normal cell undergoes many mutations during tumorigenesis. One of the features of this process is the loss of control over proliferation. Typically this loss is the result of mutations in two types of genes, oncogenes and tumor suppressor genes. The products of oncogenes normally act to promote cell division, and mutation of these genes leads to inappropriate signals to divide. The protein products of tumor suppressor genes act to limit the proliferation of a normal cell. During tumorigenesis these genes are often inactivated through mutation, and it is the loss of tumor suppressor gene products that contributes to increased proliferation. One of the first tumor suppressor genes to be isolated was the retinoblastoma susceptibility gene, RB-1. Retinoblastomas characteristically contain two rate limiting mutations, one in each allele of RB-1. In familial retinoblastomas, one mutant allele is inherited and the other develops during somatic development of the retina. In sporadic retinoblastomas, both mutations occur during somatic development. RB-1 mutations have also been found in a wide variety of other human tumors. This work leads to the conclusion that the product of the RB-1 gene negatively regulates proliferation of many different types of cell. Recent studies of the protein product of the RB-1 gene (pRB) have provided the first clues to its function. It is a nuclear protein whose normal role appears to be the regulation of certain cellular transcription factors. The best characterized partner for pRB is the transcription factor E2F. E2F appears to regulate the transcription of a set of genes whose expression is required for cell proliferation. Current evidence suggests that pRB represses E2F-mediated transcription and thereby contributes to the regulation of key genes. This interaction appears to be only one component of E2F regulation. There is strong evidence that the activity of E2F is also regulated by its association with the pRB-related protein p107. pRB and p107 share many properties. They both were originally identified through their interactions with DNA tumor virus oncoproteins. Viral proteins, including adenovirus E1A, SV40 large T, and human papillomavirus E7, all target pRB and p107 as a portion of their transforming ability. In these cases, E1A, large T, and E7 inactivate pRB and p107, thus mimicking the loss of pRB in human tumors. This grant proposes to investigate how pRB, p107 and E2F combine to give regulated transactivation and to determine the biological consequences of these interactions. Our immediate goals are threefold. First, we need to understand the details of pRB/E2F regulation. This work is currently underway and encompasses the biochemistry of pRB/E2F regulation, the determination of the effects of upstream regulators and the analysis of downstream targets. The second main goal is to determine how p107 affects E2F transcription. Most of the reagents needed for these studies are now available and we have established the basic assays. The biological consequences of these interactions are our third goal. Here, we will determine how these proteins contribute to the regulation of cell proliferation, differentiation, and oncogenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cellular Biology and Physiology Subcommittee 1 (CBY)
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Massachusetts General Hospital
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Wu, C L; Classon, M; Dyson, N et al. (1996) Expression of dominant-negative mutant DP-1 blocks cell cycle progression in G1. Mol Cell Biol 16:3698-706
Yamasaki, L; Jacks, T; Bronson, R et al. (1996) Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85:537-48