Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP
Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP
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DOI：
10.1016/s0092-8674(03)00802-x
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发表时间：
2003-10-17
期刊：
影响因子：
64.5
通讯作者：
Goodman, RH
中科院分区：
文献类型：
--
作者：
Zhang, OH;Yoshimatsu, Y;Goodman, RH
基因敲除小鼠胚胎成纤维细胞中转录辅抑制因子CtBP上调参与细胞凋亡的几个基因。因此，我们预测，细胞凋亡的倾向可能通过细胞CtBP的变化来调节。为了确定参与这种调节的途径，我们用E1 A-CtBP复合物筛选了小鼠胚胎cDNA文库，并确定了同源结构域相互作用蛋白激酶2（HIPK 2），该蛋白激酶2先前通过其磷酸化p53的能力与UV介导的凋亡相关。HIPK 2的表达或暴露于UV照射通过蛋白体介导的途径降低CtBP水平。通过共表达激酶失活的HIPK 2或通过siRNA降低HIPK 2水平来防止UV效应。HIPK 2磷酸化残基的突变阻止UV和HIPK 2指导的CtBP清除。最后，通过基因敲除或siRNA降低CtBP水平，促进p53缺陷细胞的凋亡。这些发现为缺乏p53的细胞中UV诱导的凋亡提供了途径。
Genetic knockout of the transcriptional corepressor CtBP in mouse embryo fibroblasts upregulates several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP. To identify pathways involved in this regulation, we screened a mouse embryo cDNA library with an E1A-CtBP complex and identified the homeodomain interacting protein kinase 2 (HIPK2), which had previously been linked to UV-directed apoptosis through its ability to phosphorylate p53. Expression of HIPK2 or exposure to UV irradiation reduced CtBP levels via a proteosome-mediated pathway. The UV effect was prevented by coexpression of kinase-inactive HIPK2 or reduction in HIPK2 levels via siRNA. Mutation of the residue phosphorylated by HIPK2 prevented UV- and HIPK2-directed CtBP clearance. Finally, reduction in CtBP levels, either by genetic knockout or siRNA, promoted apoptosis in p53-deficient cells. These findings provide a pathway for UV-induced apoptosis in cells lacking p53.