Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 24, Issue 10, Pages 4438-4447Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.10.4438-4447.2004
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Funding
- NCI NIH HHS [R01 CA077314-07, R01 CA077314-06, CA58320, R01 CA077314, R01 CA043054, R01 CA058320, R37 CA043054] Funding Source: Medline
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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-a following RB degradation. In cells expressing a degradation-resistant RB protein (RIB-MI), TNF-a does not activate c-ABL. RB-MI also inhibits TNF-alpha-mediated activation of p73. Genetic deletion and pharmacological inhibition of c-A-BL or p73 diminish the apoptotic response to TNF-alpha in human cell lines and mouse fibroblasts. Thymocytes isolated from Rb-MI/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.
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