Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence.
Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence.
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作者：
细胞衰老最近已被证明在对抗肿瘤发生和促进中起重要作用。由癌基因或肿瘤抑制基因的丢失诱导的衰老被认为严重依赖于p19 Arf-p53通路的诱导。Skp 2 E3-泛素连接酶可以作为原癌基因，其异常过表达经常在人类癌症中观察到。在这里，我们表明，虽然Skp 2本身的失活不会诱导细胞衰老，异常的原癌基因信号以及肿瘤抑制基因的失活确实触发了小鼠和缺乏Skp 2的细胞的有效的肿瘤抑制衰老反应。值得注意的是，Skp 2失活和致癌应激驱动的衰老既不促进p19 Arf-p53通路的激活，也不导致DNA损伤，而是依赖于ATF 4、p27和p21。我们进一步证明，即使在p19 Arf/p53反应受损的致癌条件下，遗传Skp 2失活也会引起细胞衰老，而Skp 2-SCF复合物抑制剂可以在临床前研究中触发p53/PTEN缺陷细胞的细胞衰老和肿瘤消退。因此，我们的研究结果提供了Skp 2药理学抑制可能代表癌症预防和治疗的一般方法的原则证据。
Cellular senescence has been recently shown to play an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or loss of tumour suppressor genes is thought to critically dependent on the induction of the p19Arf-p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumor-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic stress driven senescence neither elicits activation of the p19Arf-p53 pathway nor DNA damage, but instead depends on ATF4, p27, and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19Arf/p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/PTEN deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof of principle evidence that Skp2 pharmacological inhibition may represent a general approach for cancer prevention and therapy.
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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：
7.3
作者：
Chen Z;Carracedo A;Lin HK;Koutcher JA;Behrendt N;Egia A;Alimonti A;Carver BS;Gerald W;Teruya-Feldstein J;Loda M;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
11.4
作者：
Kuo, Yu-Liang;Giam, Chou-Zen
通讯作者：
Giam, Chou-Zen
影响因子：
14.5
作者：
Bloom, J;Pagano, M
通讯作者：
Pagano, M