Tumor necrosis factor alpha-induced apoptosis requires p73 and c-ABL activation downstream of RB degradation.
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 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.
Chau
B Nelson
BN
Division of Biological Sciences and Cancer Center, University of California, San Diego, La Jolla, California 92093-0322, USA.
Chen
Tung-Ti
TT
Wan
Yisong Y
YY
DeGregori
James
J
Wang
Jean Y J
JY
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D016313:Genes, abl; D016158:Genes, p53; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D020169:Caspases