Phosphorylation of Par-4 by protein kinase a is critical for apoptosis
Phosphorylation of Par-4 by protein kinase a is critical for apoptosis
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DOI：
10.1128/mcb.25.3.1146-1161.2005
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发表时间：
2005-02-01
影响因子：
5.3
通讯作者：
Rangnekar, VM
中科院分区：
文献类型：
--
作者：
Gurumurthy, S;Goswami, A;Rangnekar, VM
尽管有明显的不同之处，但不同的癌症表现出几个共同的促癌特征。我们在此提出的证据表明，促凋亡蛋白PAR-4利用一种常见的致癌特性选择性地激活并诱导癌细胞的凋亡。癌细胞中蛋白激酶A(PKA)活性的升高激活了异位PAR-4或其SAC结构域的凋亡功能，选择性地诱导癌细胞的凋亡，而不是正常或永生化细胞的凋亡。在癌细胞中，PKA优先在SAC结构域内的T155残基上磷酸化PAR-4。此外，药物、多肽或小干扰RNA介导的对癌细胞中PKA活性的抑制导致了PAR-4对T155磷酸化和细胞凋亡的抑制。内源性PAR-4的激活机制与异位PAR-4相似，内源性PAR-4对外界刺激的反应是通过依赖PKA和磷酸化T155的机制诱导细胞凋亡。正常细胞中PKA活性的增强导致PAR-4的SAC结构域以T155依赖的方式诱导细胞凋亡。综上所述，这些观察表明，PAR-4的SAC结构域对癌细胞的选择性凋亡涉及PKA对T155的磷酸化。这些发现揭示了一种新的机制，即利用PKA激活PAR-4的癌症选择性凋亡作用。PKA是一种在大多数肿瘤细胞中普遍升高的癌前活性。
Despite distinct dissimilarities, diverse cancers express several common protumorigenic traits. We present here evidence that the proapoptotic protein Par-4 utilizes one such common tumorigenic trait to become selectively activated and induce apoptosis in cancer cells. Elevated protein kinase A (PKA) activity noted in cancer cells activated the apoptotic function of ectopic Par-4 or its SAC (selective for apoptosis induction in cancer cells) domain, which induces apoptosis selectively in cancer cells and not in normal or immortalized cells. PKA preferentially phosphorylated Par-4 at the T155 residue within the SAC domain in cancer cells. Moreover, pharmacological-, peptide-, or small interfering RNA-mediated inhibition of PKA activity in cancer cells resulted in abrogation of both T155 phosphorylation and apoptosis by Par-4. The mechanism of activation of endogenous Par-4 was similar to that of ectopic Par-4, and in response to exogenous stimuli, endogenous Par-4 induced apoptosis by a PKA- and phosphorylated T155-dependent mechanism. Enforced elevation of PKA activity in normal cells resulted in apoptosis by the SAC domain of Par-4 in a T155-dependent manner. Together, these observations suggest that selective apoptosis of cancer cells by the SAC domain of Par-4 involves phosphorylation of T155 by PKA. These findings uncover a novel mechanism engaging PKA, a procancerous activity commonly elevated in most tumor cells, to activate the cancer selective apoptotic action of Par-4.