Tumor necrosis factor alpha-induced apoptosis requires p73 and c-ABL activation downstream of RB degradation
Tumor necrosis factor alpha-induced apoptosis requires p73 and c-ABL activation downstream of RB degradation
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DOI：
10.1128/mcb.24.10.4438-4447.2004
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发表时间：
2004-05-01
影响因子：
5.3
通讯作者：
Wang, JYJ
中科院分区：
文献类型：
--
作者：
Chau, BN;Chen, TT;Wang, JYJ
视网膜母细胞瘤蛋白（RB）抑制细胞增殖和凋亡。我们先前已经表明RB降解是肿瘤坏死因子α（TNF-α）诱导细胞凋亡所必需的。我们在这里展示了两种凋亡效应物的鉴定，即，c-ABL酪氨酸激酶和p73，它们在RB降解后被TNF-α激活。在表达抗降解RB蛋白（RIB-MI）的细胞中，TNF-α不激活c-ABL 13 RB-MI还抑制TNF-α介导的p73激活。c-A-BL或p73的遗传缺失和药理学抑制减少了人细胞系和小鼠成纤维细胞中对TNF-α的凋亡反应。从Rb-MI/MI、Abl（-/-）或p73（-/-）小鼠分离的胸腺细胞与其野生型对应物相比对TNF-α诱导的凋亡具有抗性。这与p53（-/-）胸腺细胞形成对比，p53（-/-）胸腺细胞响应于TNF-α而表现出野生型水平的凋亡。因此，c-ABL和p73除了在促进DNA损伤相关的细胞死亡中起作用之外，还有助于TNF-α诱导的细胞凋亡。
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.