Abstract 2178: Survivin appears to act as a transcription factor or co-factor to transcriptionally downregulate p21 gene expression via a p53 status-dependent manner

Abstract

Abstract Survivin, a unique member of the inhibitor of apoptosis (IAP) family proteins, is highly expressed in cancers but undetectable in most normal adult tissue. Survivin shows both inhibition of apoptosis and promotion of cell division. It plays a central role in cancer cell signaling network. Recent studies indicate that survivin may also play an important role in G1/S transition during cell cycle regulation. However, the underlying mechanism is unclear. Furthermore, although upregulation of p21WAF1/CIP1 (p21) expression by p53 plays an important role in p53-mediated cell G1 arrests in response to various distressing stimuli, it is unknown whether survivin plays a role in the regulation of p21 expression. Here, we report that forced expression of survivin in p53-wild type MCF-7 breast cancer cells inhibits the expression of the cell cycle inhibitor p21 protein, mRNA and promoter activity, while the survivin C84A mutant and survivin antisense failed to do so. Cotransfection experiments in the p53 mutant H1650 lung cancer cell line showed that exogenous survivin expression neutralizes p53-induced p21 expression and promoter activity. Both p53 and survivin interacts on two p53 binding sites in the p21 promoter (−2313 to -2212; -1452 to -1310), and survivin protein physically interacts with p53 protein in cancer cells. Additionally, we identified a PKC phosphorylation site at T127 that plays a critical role in inhibition of p21 promoter activity by survivin. Together, we propose that survivin acts as a transcription factor or cofactor to interact with p53 on the p21 promoter leading to transcriptional inhibition of p21 expression at least in part by neutralizing p53-mediated transcriptional activation of the p21 gene. *LT was a pre-doctoral Chinese fellowship student (Second West China Hospital, Sichuan University, Sichuan 610041, China) at the time this work was performed in the Li laboratory Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2178. doi:10.1158/1538-7445.AM2011-2178