Abstract 1140: C/ebp beta represses Arf induction by tgf-beta2

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 8_Supplement; p. 1140
• Main Authors: Zheng, Yanbin, Chu, Patricia, Skapek, Stephen X.
• Format: Journal Article
• Language: English
• Published: 15.04.2011
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-1140

Abstract Arf is a bona fide tumor suppressor that regulates cell proliferation through p53-dependent and -independent mechanisms. Recent studies show that Arf also has physiological functions in addition to tumor repression. Our group reported that the Arf promoter is strictly controlled during development and Tgf-beta2 is required for Arf promoter activation at several sites in the developing mouse. In a cell culture-based model, Arf induction by Tgf-beta depends on Smads 2/3 and p38 MAPK. But the transcription factors influenced by these signaling pathways are not yet clear. Using a candidate-gene approach, we have identified C/ebp beta as a negative Arf regulator, modified by Tgf-beta 2. The ability of Tgf-beta2 to increase p19Arf expression in wild-type mouse embryo fibroblasts (MEFs) and Arf promoter activity in Arf lacZ/lacZ MEFs correlated with repression of C/ebp beta. Pre-incubation of MEFs with SB431542, a Tgf-beta type I receptor inhibitor, blocked C/ebp beta repression and Arf induction. Retrovirus-mediated ectopic C/ebp beta blocked Arf induction by Tgf-beta2 in Arf lacZ/lacZ and wild-type MEFs. Similarly, RNAi-driven knock-down of C/ebp beta augmented Arf promoter activation by Tgf-beta2. Chromatin immunoprecipitation revealed that C/ebp beta binding to the Arf promoter after Arf promoter is initially activated by Tgf-beta2, and the binding dropped at 48 hours, when Arf expression was significantly induced. In summary, our results indicate that C/ebp beta is modified by and contributes to Arf regulation by Tgf-beta2. In contrast, the p38 MAPK inhibitor SB203580 did not influence C/ebp beta levels but still interfered with Arf induction. We are currently exploring the importance of C/ebp beta in Arf regulation by other signals and in other cell types, and investigating its importance in vivo in the developing mouse. 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 1140. doi:10.1158/1538-7445.AM2011-1140