Abstract LB-110: CDK4 activation is a key step in ELF alteration and haploinsufficeny of cdk4 prevents HCC formation in elf+/− mice

Abstract

Abstract Transforming growth factor (TGF-) is an important regulator of cell growth and the loss of TGF- signaling occurs early in carcinogenesis. Embryonic liver fodrin (ELF), an interaction protein of Smads, is involved in TGF- signaling. Significantly, elf+/− mice spontaneously developed the hepatocellular cancer (HCC) and lots of human HCC exhibited decreased or absent ELF expression. Here, we investigated how alteration of ELF led the deregulation of cell cycle progression and eventually formed the HCC. Up regulation of ELF expression led the decreased phosphorylation of Rb protein with the remarkable reduction of CDK4 than other CDKs and cyclins. Then, inhibition and downregulation of CDK4 by inhibitor and siRNA rescued the abnormality of G1/S transition and over-activation of Rb phosphorylation caused by infection of ELF shRNA in SNU475 HCC cell line. We further demonstrated the biochemical communications using immunoprecipitation that ELF interacted CDK4, and Smad3 in competitive way and TGF-ß-dependent manner. In addition, haploinsufficieny of cdk4 in elf+/− mice displayed the dramatic decrement of HCC formation than elf+/− mice with decreased Ki-67 and c-myc expressed hepatocyte in liver tissue. Thus, in response to ELF deficiency, the activation of CDK4 contributes to the phosphorylation of Rb protein, which leading to facilitated G1/S transition. Our data highlight CDK4 as an attractive target for pharmacologic inhibition and importance of elf+/− model to demonstrate pre-clinical efficacy in the treatment of HCC with ELF alteration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-110.