E2F1对MDM2-p53负反馈通路的影响
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摘要
MDM2蛋白水平被过表达的E2F所抑制,但是机制并不清楚。我们发现,在U2OS细胞里E2F1能够抑制MDM2启动子活性进而抑制MDM2蛋白水平。尽管我们发现E2F1在MDM2启动子上有高度保守的结合序列,并且E2F1能够与部分高度保守的序列结合,但是E2F1抑制MDM2启动子活性并不是通过这种启动子上的直接结合来介导的。只有在P53存在的情况下E2F1才能抑制MDM2启动子活性。在P53野生型细胞U2OS中抑制P53的表达,能够降低E2F1对MDM2启动子的抑制能力。在P53缺失型细胞H1299中,只有表达P53后E2F1才能够抑制MDM2启动子的活性。在DNA损伤刺激下P53和E2F1都被上调,我们用siRNA抑制内源E2F1表达后发现,DNA损伤刺激下上调的E2F1能够抑制MDM2启动子的活性,进而促进P53的稳定。对MDM2的抑制能够促进E2F1诱导的细胞凋亡。我们的实验结果提示了E2F1通过抑制P53对MDM2的上调来调控MDM2-P53负反馈通路的途径。
缺氧刺激能激活P53并诱导细胞凋亡,但是P53在缺氧条件下和其它DNA损伤刺激下的激活模式不相同,缺氧条件下P53丧失了转录激活的能力。我们发现MYH9和P53结合,这种结合被缺氧环境破坏。MYH9的马达结构域和P53在细胞核中结合,这种结合受到P53的磷酸化状况的调控。原核表达的P53蛋白对缺氧和正常氧浓度下的细胞裂解液中的MYH9表现出相同的亲和力,CIAP去磷酸化P53后P53重新获得了在缺氧条件下结合MYH9的能力。siRNA-MYH9抑制内源MYH9蛋白水平后P53的多个转录激活靶基因的转录活性都有下调。由于MYH9在缺氧条件下丧失与p53的结合能力,而p53在缺氧条件下丧失转录激活能力,这说明MYH9可能是P53的一个共转录激活因子,并且它的活性被缺氧条件所抑制。
MDM2 expression is down-regulated upon E2F1 over-expression, but the mechanism is not well defined. In the current study, we found that E2F1 inhibits MDM2 expression by suppressing its promoter activity. Although E2F1 binds to the MDM2 promoter, the inhibitory effect of E2F1 on the MDM2 promoter does not require the direct binding. We demonstrate that E2F1 inhibits MDM2 promoter activity in a p53-dependent manner. Knockdown of p53 in U2OS cells impairs the inhibitory effect of E2F1 on the MDM2 promoter. Consistent with this observation, E2F1 does not inhibit MDM2 promoter activity in p53-deficient H1299 cells, and the inhibition is restored when p53 is expressed exogenously. Both E2F1 and p53 are upregulated after DNA damage stimulation. We show that such stimulation induces E2F1 to inhibit MDM2 promoter activity and promote p53 accumulation. Furthermore, inhibition of MDM2 by E2F1 promotes E2F1 induced apoptosis. These data suggest that E2F1 regulates the MDM2-p53 pathway by inhibiting p53 induced up-regulation of MDM2.
Hypoxia stimulation can activate P53 and induce apoptosis, but P53 activation pattern is different from other DNA damage stimulation, P53 lost its transactivation capability. In our study we found that P53 binds with MYH9 and this binding is disrupted by hypoxia treatment. MYH9 motor domain binds with P53 in nuclear and this binding is regulated by P53 photosphorylation level. Prokaryotic expressed P53 protein shows no difference binding activity with MYH9 treated normoxia or hypoxia. CIAP de-photosphorylate P53 and gain P53 capbility in binding with MYH9 after hypoxia treatment. After knocking down MYH9 with siRNA-MYH9 in HCT116 p53+/+ cells P53 lost its transactivation activiy on some of its target genes. As P53 lost its binding activity with MYH9 under hypoxia treatment and also its transactivation capability, we perform MYH9 as a new P53 co-activator and its activity is repressed by hypoxia treatment.
缺氧刺激能激活P53并诱导细胞凋亡,但是P53在缺氧条件下和其它DNA损伤刺激下的激活模式不相同,缺氧条件下P53丧失了转录激活的能力。我们发现MYH9和P53结合,这种结合被缺氧环境破坏。MYH9的马达结构域和P53在细胞核中结合,这种结合受到P53的磷酸化状况的调控。原核表达的P53蛋白对缺氧和正常氧浓度下的细胞裂解液中的MYH9表现出相同的亲和力,CIAP去磷酸化P53后P53重新获得了在缺氧条件下结合MYH9的能力。siRNA-MYH9抑制内源MYH9蛋白水平后P53的多个转录激活靶基因的转录活性都有下调。由于MYH9在缺氧条件下丧失与p53的结合能力,而p53在缺氧条件下丧失转录激活能力,这说明MYH9可能是P53的一个共转录激活因子,并且它的活性被缺氧条件所抑制。
MDM2 expression is down-regulated upon E2F1 over-expression, but the mechanism is not well defined. In the current study, we found that E2F1 inhibits MDM2 expression by suppressing its promoter activity. Although E2F1 binds to the MDM2 promoter, the inhibitory effect of E2F1 on the MDM2 promoter does not require the direct binding. We demonstrate that E2F1 inhibits MDM2 promoter activity in a p53-dependent manner. Knockdown of p53 in U2OS cells impairs the inhibitory effect of E2F1 on the MDM2 promoter. Consistent with this observation, E2F1 does not inhibit MDM2 promoter activity in p53-deficient H1299 cells, and the inhibition is restored when p53 is expressed exogenously. Both E2F1 and p53 are upregulated after DNA damage stimulation. We show that such stimulation induces E2F1 to inhibit MDM2 promoter activity and promote p53 accumulation. Furthermore, inhibition of MDM2 by E2F1 promotes E2F1 induced apoptosis. These data suggest that E2F1 regulates the MDM2-p53 pathway by inhibiting p53 induced up-regulation of MDM2.
Hypoxia stimulation can activate P53 and induce apoptosis, but P53 activation pattern is different from other DNA damage stimulation, P53 lost its transactivation capability. In our study we found that P53 binds with MYH9 and this binding is disrupted by hypoxia treatment. MYH9 motor domain binds with P53 in nuclear and this binding is regulated by P53 photosphorylation level. Prokaryotic expressed P53 protein shows no difference binding activity with MYH9 treated normoxia or hypoxia. CIAP de-photosphorylate P53 and gain P53 capbility in binding with MYH9 after hypoxia treatment. After knocking down MYH9 with siRNA-MYH9 in HCT116 p53+/+ cells P53 lost its transactivation activiy on some of its target genes. As P53 lost its binding activity with MYH9 under hypoxia treatment and also its transactivation capability, we perform MYH9 as a new P53 co-activator and its activity is repressed by hypoxia treatment.
引文
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