Deregulated inhibition of programmed cell death (apoptosis) promotes cancer by aberrantly extending cell viability and facilitating the accumulation of mutations. Despite the identification of several apoptosis inhibitors of the bcl-2 and IAP gene family, it is uncear if apoptosis inhibition is a general growth-advantage property of cancer cells. Recently, they have identified a new human gene, designated survivin, which encodes a stricturally unique IAP apoptosis inhibitor. Prominently expressed during embryonic development, survivin is down-regulated and undetectable in normal adult tissues, and becomes abundantly re-expressed in transformed cells and in all the most common human cancers of lung, colon, pancreas, breast and prostate, in vivo. In high-grade non-Hodgkin's lymphoma and neuroblastoma, survivin expression strongly correlates with a more aggressive disease and a poor prognostic outcome. Therefore, the hypothesis that survivin can function as a new regulator of cancer cell viability can be formulated, and will constitute the focus of the present application. The first specific aim will elucidate the breadth of the anti-apoptosis function of survivin in response to oncogene expression, cytotoxic signals and chemotherapeutic drugs and irradiation. The second specific aim will dissect the structure-function relationship of survivin and identify potential survivin-associated molecules involved in the anti-apoptosis function. The third specific aim will elucidate the regulatory mechanisms of survivin gene expression with respect to minimal promoter sequences, cell proliferation/differentiation and oncogene signaling. The overall proposal is designed to shed lights into a novel survival mechanism selectively operated by cancer cells and potentially contributing to disease progression and resistance to therapy. This will facilitate the design of targeted inhibitors of this anti-apoptosis pathway, capable of disrupting cancer cell survival without affecting viability of normal cells.
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