Soluble Guanylyl Cyclase α1 and p53 Cytoplasmic Sequestration and Down-Regulation in Prostate Cancer
Soluble Guanylyl Cyclase α1 and p53 Cytoplasmic Sequestration and Down-Regulation in Prostate Cancer
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DOI：
10.1210/me.2010-0394
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发表时间：
2012-02-01
影响因子：
--
通讯作者：
Shemshedini, Lirim
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文献类型：
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作者：
Cai, Changmeng;Hsieh, Chen-Lin;Shemshedini, Lirim
我们的实验室之前已鉴定出可溶性鸟苷酸环化酶α1（sGCα1）是一种对前列腺癌细胞增殖至关重要的新型雄激素调节基因。 sGC α 1 表达在前列腺肿瘤中高度升高，与 sGC α 1 的低表达形成对比，sGC α 1 与后者二聚化以介导一氧化氮 (NO) 信号传导。在研究其作用机制时，我们发现 sGC α 1 可以抑制前列腺癌细胞中 p53 的转录活性，不依赖于 NO 信号传导的经典介质或 sGC α 1 的鸟苷酸环化酶活性。有趣的是，sGC α 1 对 p53 调节的基因表达的抑制是基因特异性的，针对参与凋亡/细胞存活的基因。与此一致的是，sGC α1 的过度表达使前列腺癌细胞对依托泊苷（一种化疗和细胞凋亡诱导药物）更具抵抗力。免疫沉淀和免疫细胞化学分析显示前列腺癌细胞中 sGC α1 和 p53 之间存在物理和直接的相互作用。有趣的是，sGC α 1 诱导 p53 细胞质隔离，代表前列腺癌中 p53 失活的新机制。前列腺肿瘤分析显示 sGC α 1 和 p53 之间存在直接表达相关性。总的来说，这些数据表明 sGC α1 对 p53 活性的调节在前列腺癌生物学中很重要，并且可能代表了表达显着水平的 p53 的前列腺癌中 p53 下调的重要机制。 （分子内分泌学26：292-307，2012）
Our laboratory has previously identified soluble guanylyl cyclase alpha 1 (sGC alpha 1) as a novel androgen-regulated gene essential for prostate cancer cell proliferation. sGC alpha 1 expression is highly elevated in prostate tumors, contrasting with the low expression of sGC alpha 1, with which sGC alpha 1 dimerizes to mediate nitric oxide (NO) signaling. In studying its mechanism of action, we have discovered that sGC alpha 1 can inhibit the transcriptional activity of p53 in prostate cancer cells independent of either classical mediators of NO signaling or the guanylyl cyclase activity of sGC alpha 1. Interestingly, sGC alpha 1 inhibition of p53-regulated gene expression was gene specific, targeting genes involved in apoptosis/cell survival. Consistent with this, overexpression of sGC alpha 1 makes prostate cancer cells more resistant to etoposide, a chemotherapeutic and apoptosis-inducing drug. Immunoprecipitation and immunocytochemistry assays show a physical and direct interaction between sGC alpha 1 and p53 in prostate cancer cells. Interestingly, sGC alpha 1 induces p53 cytoplasmic sequestration, representing a new mechanism of p53 inactivation in prostate cancer. Analysis of prostate tumors has shown a direct expression correlation between sGC alpha 1 and p53. Collectively, these data suggest that sGC alpha 1 regulation of p53 activity is important in prostate cancer biology and may represent an important mechanism of p53 down-regulation in those prostate cancers that express significant levels of p53. (Molecular Endocrinology 26: 292-307, 2012)