PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells.
PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells.
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DOI：
10.1158/0008-5472.can-14-0872
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发表时间：
2014-10-15
期刊：
影响因子：
11.2
通讯作者：
Reed JC
中科院分区：
文献类型：
--
作者：
Yanagi T;Krajewska M;Matsuzawa S;Reed JC
PCTAIRE 1是细胞周期蛋白依赖性激酶家族的远亲，该家族与精子发生和神经元发育有关，但尚未在癌症中进行研究。在这里，我们报告了PCTAIRE 1在前列腺癌、乳腺癌和宫颈癌细胞中表达，由于中心体动力学缺陷，其RNA干扰介导的沉默会导致生长抑制和异常有丝分裂。PCTAIRE 1没有类似地参与非转化细胞的增殖，包括二倍体人IMR-90成纤维细胞。通过酵母双杂交筛选，我们确定了肿瘤抑制基因p27作为PCTAIRE 1相互作用。体外激酶试验显示PCTAIRE 1磷酸化p27的Ser 10。PCTAIRE 1沉默调节p27上的Ser 10磷酸化，并导致其在癌细胞中积累，但不在非转化细胞中积累。在PPC 1前列腺癌的小鼠异种移植模型中，PCTAIRE 1的条件性沉默恢复了p27蛋白表达并抑制了肿瘤生长。HeLa细胞中的机制研究表明，PCTAIRE 1在细胞周期的S期和M期磷酸化p27。值得注意的是，p27沉默足以拯救细胞免于由PCTAIRE 1沉默引起的有丝分裂停滞。临床上，PCTAIRE 1在原发性乳腺和前列腺肿瘤中的表达高于邻近的正常上皮组织。总之，我们的研究结果揭示了PCTAIRE 1在调节p27稳定性、有丝分裂和肿瘤生长中的意想不到的作用，表明PCTAIRE 1是一个候选的癌症治疗靶点。
PCTAIRE1 is distant relative of the cyclin-dependent kinase family that has been implicated in spermatogenesis and neuronal development, but it has not been studied in cancer. Here we report that PCTAIRE1 is expressed in prostate, breast, and cervical cancer cells where its RNAi-mediated silencing causes growth inhibition with aberrant mitosis due to defects in centrosome dynamics. PCTAIRE1 was not similarly involved in proliferation of non-transformed cells including diploid human IMR-90 fibroblasts. Through yeast two-hybrid screening we identified tumor suppressor p27 as a PCTAIRE1 interactor. In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in non-transformed cells. In a mouse xenograft model of PPC1 prostate cancer, conditional silencing of PCTAIRE1 restored p27 protein expression and suppressed tumor growth. Mechanistic studies in HeLa cells showed that PCTAIRE1 phosphorylates p27 during the S and M phases of the cell cycle. Notably, p27 silencing was sufficient to rescue cells from mitotic arrest caused by PCTAIRE1 silencing. Clinically, PCTAIRE1 was highly expressed in primary breast and prostate tumors compared to adjacent normal epithelial tissues. Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target.