Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53.
Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53.
复制标题
DOI：
10.1083/jcb.200411093
复制
发表时间：
2005-02-14
期刊：
影响因子：
--
通讯作者：
Hara E
中科院分区：
文献类型：
--
作者：
Maehara K;Yamakoshi K;Ohtani N;Kubo Y;Takahashi A;Arase S;Jones N;Hara E
E2F/DP复合物最初被认为是细胞增殖所需的有效转录激活剂。然而，最近的研究修正了这一观点，表明E2F或DP的显性阴性形式使总E2F/DP活性失活并不能阻止细胞增殖，而是消除肿瘤抑制途径，如细胞衰老。这些观察结果表明，阻断E2F/DP总活性可能会增加患癌症的风险。在这里，我们提供的证据表明，通过RNA干扰来消耗DP，而不是过度表达E2F的显性阴性形式，有效地降低了人原代细胞中内源性E2F/DP的活性。总E2F/DP活性的降低导致许多E2F靶基因的表达急剧下降，并导致类似衰老的细胞周期停滞。重要的是，在缺乏功能性p53和pRB家族蛋白的人类癌细胞中也观察到类似的结果。这些发现表明，E2F/DP活性确实对细胞增殖至关重要，其降低会立即引发类似衰老的细胞周期阻滞。
E2F/DP complexes were originally identified as potent transcriptional activators required for cell proliferation. However, recent studies revised this notion by showing that inactivation of total E2F/DP activity by dominant-negative forms of E2F or DP does not prevent cellular proliferation, but rather abolishes tumor suppression pathways, such as cellular senescence. These observations suggest that blockage of total E2F/DP activity may increase the risk of cancer. Here, we provide evidence that depletion of DP by RNA interference, but not overexpression of dominant-negative form of E2F, efficiently reduces endogenous E2F/DP activity in human primary cells. Reduction of total E2F/DP activity results in a dramatic decrease in expression of many E2F target genes and causes a senescence-like cell cycle arrest. Importantly, similar results were observed in human cancer cells lacking functional p53 and pRB family proteins. These findings reveal that E2F/DP activity is indeed essential for cell proliferation and its reduction immediately provokes a senescence-like cell cycle arrest.
登录
查看更多内容
影响因子：
5.3
作者：
Kohn, MJ;Leung, SW;Yamasaki, L
通讯作者：
Yamasaki, L
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
50.3
作者：
Rowland, BD;Denissov, SG;Peeper, DS
通讯作者：
Peeper, DS
影响因子：
46.9
作者：
Bandara, LR;Girling, R;LaThangue, NB
通讯作者：
LaThangue, NB
影响因子：
16
作者：
Dick, FA;Dyson, N
通讯作者：
Dyson, N