Yamada D, Pérez-Torrado R, Filion G, Caly M, Jammart B, Devignot V, Sasai N, Ravassard P, Mallet J, Sastre-Garau X, Schmitz M L, Defossez P-A
CNRS UMR218, Institut Curie, Paris, France.
Oncogene. 2009 Jul 9;28(27):2535-44. doi: 10.1038/onc.2009.109. Epub 2009 May 18.
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.
HIPK2是一种真核丝氨酸 - 苏氨酸激酶，可响应外源性信号控制细胞增殖和存活。在此，我们表明人类转录因子ZBTB4是HIPK2的一个新靶点。这两种蛋白质在体外相互作用、共定位并在体内缔合，并且HIPK2使ZBTB4的几个保守残基磷酸化。过表达HIPK2会导致ZBTB4降解，而过表达HIPK2的激酶缺陷型突变体则没有影响。HIPK2的化学激活也会降低细胞中ZBTB4的量。相反，药物或RNA干扰对HIPK2的抑制会导致ZBTB4水平大幅增加。HIPK2对ZBTB4的这种负调控在细胞生长的正常条件下发生。此外，DNA损伤会增加这种降解。这些发现有两个结果。首先，我们最近表明ZBTB4抑制p21的转录。因此，HIPK2对p21的激活有两个方面：刺激激活剂p53，同时抑制抑制剂ZBTB4。其次，已知ZBTB4结合甲基化DNA并抑制甲基化序列。因此，我们的发现增加了HIPK2可能影响有待确定的基因座处基因表达的表观遗传调控的可能性。
