E2F1在发育中的肿瘤细胞中依赖p53的凋亡信号传导和细胞分裂中起关键作用。

Key roles for E2F1 in signaling p53-dependent apoptosis and in cell division within developing tumors.

作者信息

Pan H, Yin C, Dyson N J, Harlow E, Yamasaki L, Van Dyke T

机构信息

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill 27599, USA.

出版信息

Mol Cell. 1998 Sep;2(3):283-92. doi: 10.1016/s1097-2765(00)80273-7.

DOI:10.1016/s1097-2765(00)80273-7

PMID:9774967

Abstract

Apoptosis induced by the p53 tumor suppressor can attenuate cancer growth in preclinical animal models. Inactivation of the pRb proteins in mouse brain epithelium by the T121 oncogene induces aberrant proliferation and p53-dependent apoptosis. p53 inactivation causes aggressive tumor growth due to an 85% reduction in apoptosis. Here, we show that E2F1 signals p53-dependent apoptosis since E2F1 deficiency causes an 80% apoptosis reduction. E2F1 acts upstream of p53 since transcriptional activation of p53 target genes is also impaired. Yet, E2F1 deficiency does not accelerate tumor growth. Unlike normal cells, tumor cell proliferation is impaired without E2F1, counterbalancing the effect of apoptosis reduction. These studies may explain the apparent paradox that E2F1 can act as both an oncogene and a tumor suppressor in experimental systems.

摘要

p53肿瘤抑制因子诱导的细胞凋亡可在临床前动物模型中减弱癌症生长。T121癌基因使小鼠脑上皮细胞中的pRb蛋白失活，会诱导异常增殖和p53依赖性细胞凋亡。p53失活会导致细胞凋亡减少85%，从而引发侵袭性肿瘤生长。在此，我们表明E2F1发出p53依赖性细胞凋亡信号，因为E2F1缺陷会导致细胞凋亡减少80%。E2F1作用于p53上游，因为p53靶基因的转录激活也会受损。然而，E2F1缺陷并不会加速肿瘤生长。与正常细胞不同，没有E2F1时肿瘤细胞增殖会受损，这抵消了细胞凋亡减少的影响。这些研究可能解释了E2F1在实验系统中既能充当癌基因又能充当肿瘤抑制因子这一明显矛盾现象。