Skp2 启动子通过 NF-κB、p53 和 Akt/GSK3β 信号通路整合信号，以调节自噬和细胞凋亡。
The Skp2 promoter integrates signaling through the NF-kappaB, p53, and Akt/GSK3beta pathways to regulate autophagy and apoptosis.
机构信息
Department of Cellular and Molecular Medicine, University of Bristol School of Medical Sciences, Bristol, UK.
出版信息
Mol Cell. 2010 May 28;38(4):524-38. doi: 10.1016/j.molcel.2010.03.018.
NF-kappaB and p53 are important regulators of the cellular response to stress. Here, we identify the Skp2 gene as being both an NF-kappaB and p53 target after DNA damage. However, Skp2 expression can be either induced or repressed in a manner requiring both the p52 NF-kappaB subunit and p53, with subsequent effects on autophagy, apoptosis, and p53 function. This process is regulated by the Akt(PKB)/GSK3beta pathway. When Akt is active, GSK3beta is repressed, allowing p52 and p53 to cooperatively induce Skp2 expression. However, if Akt is inactive, GSK3beta phosphorylates p52 at Ser 222. This modification disrupts p52 homodimer/Bcl-3 complexes and facilitates transcriptional repression by p52/-c-Rel. The Skp2 promoter therefore integrates signaling through the NF-kappaB, p53, and Akt/GSK3beta pathways to regulate cell fate in response to DNA damage.
NF-κB 和 p53 是细胞应激反应的重要调节因子。在这里，我们发现 Skp2 基因是 NF-κB 和 p53 的靶点，在 DNA 损伤后。然而，Skp2 的表达可以通过既需要 p52 NF-κB 亚基又需要 p53 的方式被诱导或抑制，随后对自噬、细胞凋亡和 p53 功能产生影响。这个过程受到 Akt(PKB)/GSK3β 通路的调节。当 Akt 活跃时，GSK3β 被抑制，允许 p52 和 p53 协同诱导 Skp2 的表达。然而，如果 Akt 不活跃，GSK3β 会磷酸化 p52 的 Ser222。这种修饰破坏了 p52 同源二聚体/Bcl-3 复合物，并促进了 p52/-c-Rel 的转录抑制。因此，Skp2 启动子整合了通过 NF-κB、p53 和 Akt/GSK3β 通路的信号传导，以调节细胞命运对 DNA 损伤的反应。
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