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p53 action in apoptosis and senescence

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Our laboratory is interested in the genes that control apoptosis and cellular senescence, two conceptually related processes that can act to limit cellular proliferation. Both processes are frequently disrupted in cancer cells, implying that each can limit tumor development. Moreover, since radiation and many chemotherapeutic agents can activate apoptosis or senescence, the integrity of these anti-proliferative programs may influence the outcome of cancer therapy in patients. The p53 tumor suppressor can promote apoptosis or senescence and, together with its cell-cycle checkpoint function, acts at in a variety of ways to protect against cancer. For example, p53 can be activated by DNA damage to activate cell-cycle checkpoints or apoptosis, such that cells lacking p53 are prone to certain forms of mutation and genomic instability. This implies that p53 can indirectly suppress tumorigenesis by acting as a `Guardian of the Genome', that is, to promote the repair or elimination of cells sustaining potentially deleterious mutations. Remarkably, since most current anticancer agents directly or indirectly damage DNA, the integrity of this p53 response may contribute to tumor cell death during therapy. In addition, certain mitogenic oncogenes activate p53 to promote apoptosis or senescence. Loss of p53 prevents these responses, leading to oncogenic transformation or tumor progression. In these settings, p53 can directly suppress tumorigenesis by acting in a fail-safe mechanism to counter hyperproliferative signals. We are currently studying many aspects of p53, including how oncogenes or DNA-damaging agents activate p53, how p53 executes a biological response, and how cellular factors influence whether p53 induces a cell-cycle checkpoint, cellular senescence, or apoptosis. We are also developing animal models to examine the impact of the p53 pathway on tumor cell responses to anticancer agents.

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Lowe, S., Schmitt, C., Ferbeyre, G. et al. p53 action in apoptosis and senescence. Breast Cancer Res 2 (Suppl 1), S.22 (2000).

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