P300 regulates p53-dependent apoptosis after DNA damage in colorectal cancer cells by modulation of PUMA/p21 levels
P300 regulates p53-dependent apoptosis after DNA damage in colorectal cancer cells by modulation of PUMA/p21 levels
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DOI：
10.1073/pnas.0401002101
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发表时间：
2004-05-11
影响因子：
11.1
通讯作者：
Caldas, C
中科院分区：
文献类型：
--
作者：
Iyer, NG;Chin, SF;Caldas, C
DNA损伤激活肿瘤抑制基因p53可诱导细胞周期停滞或凋亡，但决定细胞停滞或死亡的因素尚不清楚。在这份报告中，我们表明，E1 A结合p300核蛋白是一个关键的决定因素，p53依赖的细胞命运在结直肠癌细胞：缺乏p300增加细胞凋亡的DNA损伤。此外，p300缺陷型（p300（-））细胞在UV照射后不能经历G（1）/S停滞。这些异常与p53稳定性延长、p53乙酰化降低、MDM 2激活钝化、p21反式激活失败和p53 A水平不成比例增加有关。当异种移植时，p300（-）细胞对阿霉素化疗更敏感。这些结果表明，p300是p53反应的关键调节因子，并表明p300抑制可用于调节化疗。
Activation of the tumor suppressor p53 by DNA damage induces either cell cycle arrest or apoptosis, but what determines the choice between cytostasis and death is not clear. In this report, we show that the E1A-binding p300 nucleoprotein is a key determinant of p53-dependent cell fate in colorectal cancer cells: absence of p300 increases apoptosis in response to DNA damage. In addition, p300-deficient (p300(-)) cells fail to undergo G(1)/S arrest after UV irradiation. These abnormalities are associated with prolongation of p53 stability, reduced p53-acetylation, blunting of MDM2 activation, failure to transactivate p21, and a disproportionate increase in PUMA levels. When xenografted, p300(-) cells are more sensitive to chemotherapy with doxorubicin. These results show that p300 is a key regulator of the p53 response and suggest that p300 inhibition could be used to modulate chemotherapy.