Gadd45b Mediates Fas-induced Apoptosis by Enhancing the Interaction between p38 and Retinoblastoma Tumor Suppressor

Seung-Ho Park,Sun-Mi Park,Min-Ju Im,Seran Bae,Eun Mi Hwang,In-Koo Nam,Kyoung Eun Baek,Jae-Yong Park,Hee Jun Cho,In-Kyu Kim,Jiyun Yoo

doi:10.1074/jbc.m109.091413

Abstract

Gadd45b has been known as a positive mediator of apoptosis induced by certain cytokines and oncogenes. Here, we identified Gadd45b as an effector of Fas-induced apoptosis and found that p38-mediated Rb hyperphosphorylation is one of the mechanisms of Fas-induced apoptosis in murine hepatocyte AML12 cells. Gadd45b has been shown to activate p38 through its physical interaction with MTK1 and induce apoptosis. However, in this study, we have showed that the function of Gadd45b during Fas-induced apoptosis in AML12 cells is different from that reported in previous studies. Depletion of Gadd45b expression did not inhibit the phosphorylation of p38, but it suppressed p38-mediated Rb phosphorylation and apoptosis in response to Fas stimulation by reducing the interaction between p38 and Rb. Ectopic expression of Gadd45b was sufficient to enhance this interaction. These findings suggest that Gadd45b mediates p38-induced Rb phosphorylation by enhancing the interaction between p38 and Rb during Fas-induced apoptosis in murine hepatocytes.

Highlights

Fas (CD95/APO1) is the prototypic representative of the death receptor subgroup that belongs to the tumor necrosis factor receptor family
Ectopic expression of Gadd45b was sufficient to enhance this interaction. These findings suggest that Gadd45b mediates p38induced Rb phosphorylation by enhancing the interaction between p38 and Rb during Fas-induced apoptosis in murine hepatocytes
One major property of Gadd45 family proteins is that overexpression of each individual Gadd45 protein activates p38/ JNK MAPK and causes apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 protein, a MAPK kinase kinase upstream in the p38 pathway [11]

Summary

Introduction

Fas (CD95/APO1) is the prototypic representative of the death receptor subgroup that belongs to the tumor necrosis factor receptor family. In this study, we have showed that the function of Gadd45b during Fas-induced apoptosis in AML12 cells is different from that reported in previous studies. These findings suggest that Gadd45b mediates p38induced Rb phosphorylation by enhancing the interaction between p38 and Rb during Fas-induced apoptosis in murine hepatocytes.

Results

Conclusion