Bi-directional regulation between tyrosine kinase Etk/BMX and tumor suppressor p53 in response to DNA damage
Bi-directional regulation between tyrosine kinase Etk/BMX and tumor suppressor p53 in response to DNA damage
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DOI：
10.1074/jbc.m409108200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
Qiu, Y
中科院分区：
文献类型：
--
作者：
Jiang, TY;Guo, ZY;Qiu, Y
Etk/Bmx是Tec非受体酪氨酸激酶家族的一员，参与多种细胞过程的调控，包括增殖、分化、运动和凋亡。在这里，我们报告了通过Src同源3结构域阵列筛选确定Tec家族激酶作为肿瘤抑制因子p53的潜在相互作用蛋白。Etk通过其Src同源3结构域和p53富含脯氨酸的结构域与p53存在物理关联。DNA损伤诱导p53表达可抑制几种细胞类型中的Etk活性。通过特异性小干扰RNA下调Etk表达可使前列腺癌细胞对阿霉素诱导的凋亡敏感，表明抑制Etk活性是DNA损伤导致细胞凋亡的必要条件。我们还表明，Etk主要与细胞质中的p53相互作用，这种相互作用导致两种蛋白的活性双向抑制。前列腺癌细胞中Etk的过表达导致p53转录活性及其与线粒体蛋白BAK的相互作用受到抑制，并赋予对阿霉素的抗性。因此，我们提出在特定细胞类型中p53和Tec家族激酶之间的化学计量可能决定其对化疗药物的敏感性。
Etk/Bmx, a member of the Tec family of nonreceptor tyrosine kinases, has been implicated in the regulation of various cellular processes including proliferation, differentiation, motility, and apoptosis. Here, we report the identification of Tec family kinases as the potential interacting proteins of the tumor suppressor p53 by an Src homology 3 domain array screening. Etk is physically associated with p53 through its Src homology 3 domain and the proline-rich domain of p53. Induction of p53 expression by DNA damage inhibits Etk activity in several cell types. Down-regulation of Etk expression by a specific small interfering RNA sensitizes prostate cancer cells to doxorubicin-induced apoptosis, suggesting that inhibition of Etk activity is required for apoptosis in response to DNA damage. We also show that Etk primarily interacts with p53 in the cytoplasm and that such interaction leads to bidirectional inhibition of the activities of both proteins. Overexpression of Etk in prostate cancer cells results in inhibition of p53 transcriptional activity and its interaction with the mitochondrial protein BAK and confers the resistance to doxorubicin. Therefore, we propose that the stoichiometry between p53 and the Tec family kinases in a given cell type may determine its sensitivity to chemotherapeutic drugs.