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首页> 外文期刊>Molecular and Cellular Biology >Glycogen Synthase Kinase 3-Dependent Phosphorylation of Mdm2 Regulates p53 Abundance
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Glycogen Synthase Kinase 3-Dependent Phosphorylation of Mdm2 Regulates p53 Abundance

机译：糖原合酶激酶3依赖的Mdm2磷酸化调节p53的丰度。

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摘要

The Mdm2 oncoprotein regulates abundance and activity of the p53 tumor suppressor protein. For efficient degradation of p53, Mdm2 needs to be phosphorylated at several contiguous residues within the central conserved domain. We show that glycogen synthase kinase 3 (GSK-3) phosphorylated the Mdm2 protein in vitro and in vivo in the central domain. Inhibition of GSK-3 rescued p53 from degradation in an Mdm2-dependent manner while its association with Mdm2 was not affected. Likewise, inhibition of GSK-3 did not alter localization of p53 and Mdm2 or the interaction of Mdm2 and MdmX. Ionizing radiation, which leads to p53 accumulation, directed phosphorylation of GSK-3 at serine 9, which preceded and overlapped with the increase in p53 levels. Moreover, expression of a GSK-3 mutant where serine 9 was replaced with an alanine reduced the accumulation of p53 and induction of its target p21WAF-1. We therefore conclude that inhibition of GSK-3 contributes to hypophosphorylation of Mdm2 in response to ionizing rays, and in consequence to p53 stabilization.
机译：Mdm2癌蛋白调节p53肿瘤抑制蛋白的丰度和活性。为了有效降解p53，Mdm2需要在中央保守域内的几个连续残基处磷酸化。我们显示糖原合酶激酶3（GSK-3）磷酸化Mdm2蛋白在体外和体内的中央域。 GSK-3的抑制以依赖于Mdm2的方式使p53免受降解，同时不影响其与Mdm2的结合。同样，抑制GSK-3不会改变p53和Mdm2的定位或Mdm2和MdmX的相互作用。电离辐射导致p53积累，在丝氨酸9处引导GSK-3磷酸化，该磷酸化与p53水平的增加相重叠。此外，用丝氨酸9替换为丙氨酸的GSK-3突变体的表达减少了p53的积累并诱导了其靶标p21 WAF-1 。因此，我们得出结论，抑制GSK-3有助于Mdm2的低磷酸化，以响应电离射线，并因此导致p53稳定。

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