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Molecular and Cellular Biology, May 2004, p. 4438-4447, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4438-4447.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

B. Nelson Chau,1 Tung-Ti Chen,1,{dagger} Yisong Y. Wan,2,{ddagger} James DeGregori,2 and Jean Y. J. Wang1*

Division of Biological Sciences and Cancer Center, University of California, San Diego, La Jolla, California 92093-0322,1 Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, University of Colorado Health Sciences Center, Denver, Colorado 802622

Received 7 October 2003/ Returned for modification 21 November 2003/ Accepted 21 February 2004

The retinoblastoma protein (RB) suppresses cell proliferation and apoptosis. We have previously shown that RB degradation is required for tumor necrosis factor alpha (TNF-{alpha}) 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-{alpha} following RB degradation. In cells expressing a degradation-resistant RB protein (RB-MI), TNF-{alpha} does not activate c-ABL. RB-MI also inhibits TNF-{alpha}-mediated activation of p73. Genetic deletion and pharmacological inhibition of c-ABL or p73 diminish the apoptotic response to TNF-{alpha} in human cell lines and mouse fibroblasts. Thymocytes isolated from RbMI/MI, Abl–/–, or p73–/– mice are resistant to TNF-{alpha}-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-{alpha}. Thus, c-ABL and p73 contribute to apoptosis induced by TNF-{alpha}, in addition to their role in promoting DNA damage-associated cell death.

* Corresponding author. Mailing address: 3326 Bonner Hall, MC-0322, 9500 Gilman Dr., University of California, San Diego, La Jolla, CA 92093-0322. Phone: (858) 534-6253. Fax: (858) 822-2002. E-mail: jywang{at}ucsd.edu.

{dagger} Present address: AmProx Incorporated, Carlsbad, CA 92009.

{ddagger} Present address: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.

Molecular and Cellular Biology, May 2004, p. 4438-4447, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4438-4447.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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