Tumor Necrosis Factor Alpha-Induced Apoptosis Requires p73 and c-ABL Activation Downstream of RB Degradation

Author:

Chau B. Nelson1,Chen Tung-Ti1,Wan Yisong Y.2,DeGregori James2,Wang Jean Y. J.1

Affiliation:

1. Division of Biological Sciences and Cancer Center, University of California, San Diego, La Jolla, California 92093-0322

2. Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Abstract

ABSTRACT The retinoblastoma protein (RB) suppresses cell proliferation and apoptosis. We have previously shown that RB degradation is required for tumor necrosis factor alpha (TNF-α) to induce apoptosis. We show here the identification of two apoptotic effectors, i.e., c-ABL tyrosine kinase and p73, which are activated by TNF-α following RB degradation. In cells expressing a degradation-resistant RB protein (RB-MI), TNF-α does not activate c-ABL. RB-MI also inhibits TNF-α-mediated activation of p73. Genetic deletion and pharmacological inhibition of c-ABL or p73 diminish the apoptotic response to TNF-α in human cell lines and mouse fibroblasts. Thymocytes isolated from Rb MI/MI , Abl −/− , or p73 −/− mice are resistant to TNF-α-induced apoptosis compared to their wild-type counterparts. This is in contrast to p53 −/− thymocytes, which exhibit a wild-type level of apoptosis in response to TNF-α. Thus, c-ABL and p73 contribute to apoptosis induced by TNF-α, in addition to their role in promoting DNA damage-associated cell death.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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