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    Awarded Grants
    Regulation of the Cellular Senescence Program by RB Proteins

    Scientific Abstract:
    Human cells are subject to sporadic mutation and DNA damage throughout their lifetime. If a mutation leads to the abrupt activation of a proto-oncogene, unrestrained cell division may result, followed by tumorigenesis. However, there are tumor suppressor mechanisms to restrain the proliferation of damaged or mutated cells, including apoptosis and premature cellular senescence. Cellular senescence is the process by which somatic cells undergo a permanent and irreversible cell cycle arrest. Several stimuli can induce senescence including telomere shortening (replicative senescence), DNA damage, excessive mitogenic stimulation, and activated onco-proteins (premature senescence). Thus, senescence, like apoptosis, appears to be a cellular defense against cancer. Although surmounting the senescence program is likely requisite for tumorigenesis in many cases, relatively little is known about this important endogenous mechanism. Several recent reports have demonstrated that the retinoblastoma protein (pRb), already known to be a critical regulator of apoptosis and quiescent cell cycle arrest, is also a critical regulator of cellular senescence. Although the mechanism has not yet been extensively explored, pRb-mediated formation of heterochromatin and subsequent transcriptional silencing of many cell cycle target genes appears to be crucial for the development and stable maintenance of the senescent state. Therefore, in this study we will utilize a series of novel experiments to extensively dissect the phenomenon of premature cellular senescence, with a particular focus on pRb and the pRb-related proteins p107 and p130. Our approach will involve three aims. First, we will identify RB target genes silenced during senescence using genome-scale “location analysis” and gene expression profiling, comparing growing, quiescent, and senescent cell populations. Next, we will confirm the crucial function of the pRb protein in senescence-specific gene silencing by acute ablation of pRb in senescent cells. And lastly, we will attempt to discover the molecular mechanism of Rb-mediated gene silencing during senescence by an extensive examination of Rb-mediated chromatin modifications and heterochromatin formation at Rb target promoters. These studies will significantly advance our understanding of cell cycle control and could lead to the development of new strategies for invoking permanent cell growth arrest in the treatment of human cancer.

    Lay Abstract:
    All human cells sustain sporadic mutations and DNA damage throughout life. If mutation results in the sudden activation of a gene called a proto-oncogene, the cell may divide uncontrollably. This is the genesis of a tumor. However, there are “tumor suppressor” mechanisms for stopping the proliferation of these mutated cells, including: programmed cell death (apoptosis), temporary cell growth arrest while repairs are attempted (quiescence), and permanent cell growth arrest, which, while sparing the life of the affected cell, prevents the cell from ever diving again (senescence). These mechanisms appear important for our natural protection against cancer and are controlled by genes and proteins called tumor suppressors. However, mutations in tumor suppressors also occur, allowing cancer to be an increasingly common event in the human population. We propose to study the permanent cell cycle arrest (senescence) that occurs in normal cells in response to oncogenic mutations or DNA damage. Quiescence and apoptosis have been studied in FAR more detail than senescence, in part, because key regulators of senescence have only recently been identified. One of those regulators is the retinoblastoma protein (RB). The gene for RB is frequently mutated in breast cancer (and one-third of ALL human tumors) and loss of RB has been shown to correlate with tumor aggressiveness and poor prognosis in breast cancer patients. This strong selective pressure for cancer cells to mutate the RB gene shows that RB plays a vital role in preventing cancer. Thus, RB was the prototypical “tumor suppressor gene,” and it was first discovered in hereditary cancer of the retina, hence its name. RB is known to control quiescence AND apoptosis in response to mutations, but only recently has it been implicated in senescence as well. RB functions by blocking genes required for cells to grow and divide. The repression of these cell growth genes IS reversible during quiescence, but is NOT reversible during senescence. We propose three aims to study this phenomenon. First, we will use a genome-scale analysis to identify genes that are repressed by RB during senescence. Second, we will demonstrate that the repression of those genes by RB is crucial for senescence. Last, we will study the physical changes to DNA that RB causes when it silences genes during senescence. These experiments will provide exciting new information about RB, senescence, and cancer and will hopefully bring modern science closer to developing tools that can effectively and PERMANENTLY halt the growth of cancer cells.