CONTROL OF APOPTOSIS IN CANCER BY SURVIVIN

Yale University, New Haven CT

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Abstract

DESCRIPTION: (adapted from the investigator's abstract) 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.