Superoxide Dismutase and Transcription Factor SOX9 as Mediators of Tumor Suppression by MAC25 (IGFBP-RP1) in Prostate Cancer Cells
Annual rept. 1 Apr 2004-31 Mar 2005
WASHINGTON UNIV SEATTLE
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The hypothesis of this proposal is that The mac25lGFBP-rpl gene functions as a tumor suppressor for prostate epithelium by induction of additional genes regulating response to oxidative stress, senescence, and differentiation. One of these, SOD2, impairs tumor cell growth by detoxifying superoxides which may initiate transformation, or by interaction with growth promoting signal pathways via modulation of protein phosphorylation. Another, SOX9, induces a subset of genes required for differentiation of normal cells with reduced rates of proliferation and higher susceptibility to apoptosis. We propose to adress this hypothesis by the following four Specific aims I Determine if either SOD2 or SOX9 is necessary andlor sufficient for effective tumor suppression by mac25 2 Analyze the effects of both SOD2 and SOX9 on specific proteins and activities of cell cycle and apoptotic pathways known to be regulated by mac25 3 Analyze the interaction between mac25 and andrngenrnsponsive pathways. Production of specific proteins associated with differentiation, including cytokeratins, cadherins, CD44 and CD57, and PSA, will also be determined 4 Assess the extent to which either SOD2 or SOX9 can account for the gene expression pattem associated with tumor suppression by mac25. Herein, we report on studies that address specific aims 2 and 3.
- Medicine and Medical Research