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首页> 外文期刊>Oncogene >The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4
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The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4

机译：人类蛋白激酶HIPK2磷酸化并下调甲基结合转录因子ZBTB4

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摘要

HIPK2 is a eukaryotic Serine–Threonine kinase that controls cellular proliferation and survival in response to exogenous signals. Here, we show that the human transcription factor ZBTB4 is a new target of HIPK2. The two proteins interact in vitro, colocalize and associate in vivo, and HIPK2 phosphorylates several conserved residues of ZBTB4. Overexpressing HIPK2 causes the degradation of ZBTB4, whereas overexpressing a kinase-deficient mutant of HIPK2 has no effect. The chemical activation of HIPK2 also decreases the amount of ZBTB4 in cells. Conversely, the inhibition of HIPK2 by drugs or by RNA interference causes a large increase in ZBTB4 levels. This negative regulation of ZBTB4 by HIPK2 occurs under normal conditions of cell growth. In addition, the degradation is increased by DNA damage. These findings have two consequences. First, we have recently shown that ZBTB4 inhibits the transcription of p21. Therefore, the activation of p21 by HIPK2 is two-pronged: stimulation of the activator p53, and simultaneous repression of the inhibitor ZBTB4. Second, ZBTB4 is also known to bind methylated DNA and repress methylated sequences. Consequently, our findings raise the possibility that HIPK2 might influence the epigenetic regulation of gene expression at loci that remain to be identified.
机译：HIPK2是一种真核的丝氨酸-苏氨酸激酶，可控制细胞增殖和存活，以响应外源信号。在这里，我们显示人类转录因子ZBTB4是HIPK2的新目标。这两种蛋白质在体外相互作用，在体内共定位并缔合，而HIPK2磷酸化ZBTB4的几个保守残基。过表达HIPK2导致ZBTB4降解，而过表达HIPK2的激酶缺陷型突变体则没有作用。 HIPK2的化学激活也减少了细胞中ZBTB4的数量。相反，药物或RNA干扰对HIPK2的抑制作用会导致ZBTB4水平大量增加。 HIPK2对ZBTB4的这种负调控是在正常细胞生长条件下发生的。另外，DNA损伤增加了降解。这些发现有两个后果。首先，我们最近显示ZBTB4抑制p21的转录。因此，HIPK2对p21的激活是两方面的：刺激激活剂p53，同时抑制抑制剂ZBTB4。其次，还已知ZBTB4结合甲基化DNA并抑制甲基化序列。因此，我们的发现提高了HIPK2可能影响尚待确定的基因座上基因表达的表观遗传学调控的可能性。

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