Abstract A52: Tyrosine kinase activity of c-Abl is essential for p53 dependent transactivation of p21Waf1/Cip1

Abstract

Abstract c-Abl non-receptor tyrosine kinase is a pivotal upstream positive modulator in cellular response to DNA damage, which attributes to the activation of p53 tumor suppressor protein, hence the expression of the p53 target proteins promoting growth arrest and apoptosis. Nevertheless, the comprehensive function of c-Abl in the activation of p53 mediated by phosphorylation and acetylation is still largely elusive. Thus, in an attempt to determine the significance of tyrosine kinase activity of c-Abl in p53 activation, we examined the extent of p53 activation by exposing cells to Adriamycin (ADR). Under the presence of Abl kinase inhibitor, STI571, p53 dependent transactivation of p21 and Ser15/20 phosphorylation of p53 were markedly impaired. Furthermore, overexpression of the wild type c-Abl in ADR treated cells led to marked increase in p21 expression, whereas that of tyrosine kinase deficient c-Abl led to striking decrease. When U2OS cells were treated with increasing (0, 5, 10 & 15 μM) concentration of STI571, p21 expression gradually diminished with increasing concentration of STI571. In response to DNA damage Atm activates c-Abl, which in turn tyrosine phosphorylates and activates Atm making a positive feedback loop between Atm and c-Abl. We speculate the kinase activity of c-Abl is prerequisite to potentiate Atm activity by this feedback loop resulting in the augmented activation of p53. Preliminary experiments revealed that c-Abl abrogated deacetylation of p53 and Histone protein at p53 target genes promoter mediated by Histone deacetylases (HDACs). Detailed descriptions and significance of these observations will be discussed at the meeting. Citation Format: S. M. Nashir Udden, Masanobu Satake, Shuntaro Ikawa. Tyrosine kinase activity of c-Abl is essential for p53 dependent transactivation of p21Waf1/Cip1. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A52.