Proapoptotic function of the retinoblastoma tumor suppressor protein.
Proapoptotic function of the retinoblastoma tumor suppressor protein.
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DOI：
10.1016/j.ccr.2009.01.026
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发表时间：
2009-03-03
期刊：
影响因子：
50.3
通讯作者：
Lees JA
中科院分区：
文献类型：
--
作者：
Ianari A;Natale T;Calo E;Ferretti E;Alesse E;Screpanti I;Haigis K;Gulino A;Lees JA
视网膜母细胞瘤蛋白（pRB）肿瘤抑制因子通过抑制E2 F转录因子来阻断细胞增殖。这种抑制通过有丝分裂原诱导的pRB磷酸化，触发E2 F释放和细胞周期基因的激活而缓解。E2 F1还可以激活促凋亡基因，以响应遗传毒性或致癌应激。然而，在这方面，国家预算局的作用尚未确定。在这里，我们表明，DNA损伤和E1 A诱导的致癌应激促进形成的pRB-E2 F1复合物，即使在增殖细胞。此外，pRB与具有转录活性的促凋亡启动子结合，并且pRB是体外和体内最大凋亡反应所需的。总之，这些数据揭示了pRB在诱导细胞凋亡中的直接作用，以响应遗传毒性或致癌性应激。在许多人类肿瘤中，pRB功能通过Rb基因的失活或其上游调控因子的改变而被破坏。pRB的肿瘤抑制活性至少部分地依赖于其通过E2 F抑制来阻滞细胞的能力。我们的数据现在建立了第二个作用pRB作为一个应激诱导的细胞凋亡激活剂。值得注意的是，pRB的能力，以促进任何逮捕与凋亡似乎是上下文依赖性的，与凋亡是有利于增殖细胞。这一发现有可能解释为什么细胞在停滞状态下通常更能抵抗凋亡。最重要的是，我们的观察结果表明，Rb状态将影响肿瘤对化疗的反应，通过损害逮捕和凋亡检查点的反应。
The retinoblastoma protein (pRB) tumor suppressor blocks cell proliferation by repressing the E2F transcription factors. This inhibition is relieved through mitogen-induced phosphorylation of pRB, triggering E2F release and activation of cell cycle genes. E2F1 can also activate pro-apoptotic genes in response to genotoxic or oncogenic stress. However, pRB’s role in this context has not been established. Here we show that DNA damage and E1A-induced oncogenic stress promotes formation of a pRB-E2F1 complex even in proliferating cells. Moreover, pRB is bound to pro-apoptotic promoters that are transcriptional active and pRB is required for maximal apoptotic response in vitro and in vivo. Together, these data reveal a direct role for pRB in the induction of apoptosis in response to genotoxic or oncogenic stress. SIGNIFICANCE pRB function is disrupted in many human tumors through either inactivation of the Rb gene or alterations in its upstream regulators. pRB’s tumor suppressive activity is at least partially dependent upon its ability to arrest cells through E2F inhibition. Our data now establish a second role for pRB as a stress-induced activator of apoptosis. Notably, pRB’s ability to promote either arrest versus apoptosis seems to be context dependent, with apoptosis being favored in proliferating cells. This finding has the potential to explain why cells are typically more resistant to apoptosis when in the arrested state. Most importantly, our observations suggest that Rb status will influence tumor response to chemotherapy by impairing both the arrest and apoptotic checkpoint responses.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
8
作者：
Knudsen, KE;Weber, E;Knudsen, ES
通讯作者：
Knudsen, ES
影响因子：
7.5
作者：
Iaquinta, Phillip J.;Lees, Jacqueline A.
通讯作者：
Lees, Jacqueline A.
影响因子：
20.3
作者：
Gery, S;Gombart, AF;Koeffler, HP
通讯作者：
Koeffler, HP