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Dynamic SUMOylation Is Linked to the Activity Cycles of Androgen Receptor in the Cell Nucleus

机译:动态SUMOylation链接到细胞核中的雄激素受体的活动周期。

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Despite of the progress in the molecular etiology of prostate cancer, the androgen receptor (AR) remains the major druggable target for the advanced disease. In addition to hormonal ligands, AR activity is regulated by posttranslational modifications. Here, we show that androgen induces SUMO-2 and SUMO-3 (SUMO-2/3) modification (SUMOylation) of the endogenous AR in prostate cancer cells, which is also reflected in the chromatin-bound receptor. Although only a small percentage of AR is SUMOylated at the steady state, AR SUMOylation sites have an impact on the receptor's stability, intranuclear mobility, and chromatin interactions and on expression of its target genes. Interestingly, short-term proteotoxic and cell stress, such as hyperthermia, that detaches the AR from the chromatin triggers accumulation of the SUMO-2/3-modified AR pool which concentrates into the nuclear matrix compartment. Alleviation of the stress allows rapid reversal of the SUMO-2/3 modifications and the AR to return to the chromatin. In sum, these results suggest that the androgen-induced SUMOylation is linked to the activity cycles of the holo-AR in the nucleus and chromatin binding, whereas the stress-induced SUMO-2/3 modifications sustain the solubility of the AR and protect it from proteotoxic insults in the nucleus.
机译:尽管前列腺癌的分子病因学有所进展,但雄激素受体(AR)仍然是晚期疾病的主要药物靶标。除激素配体外,AR活性还受翻译后修饰的调节。在这里,我们表明雄激素诱导前列腺癌细胞内源性AR的SUMO-2和SUMO-3(SUMO-2 / 3)修饰(SUMOylation),这也反映在染色质结合受体上。尽管只有一小部分的AR在稳态下被SUMO酰化,但AR SUMO酰化位点会影响受体的稳定性,核内迁移率和染色质相互作用以及其靶基因的表达。有趣的是,短期蛋白毒性和细胞应激(例如高热)使AR与染色质脱离,触发了SUMO-2 / 3修饰的AR池的积累,该池集中到核基质区室中。应力的减轻允许SUMO-2 / 3修饰的快速逆转,并且AR返回到染色质。总而言之,这些结果表明雄激素诱导的SUMO酰化作用与全AR在核和染色质结合中的活动周期有关,而应力诱导的SUMO-2 / 3修饰则维持了AR的溶解性并对其进行保护。来自蛋白毒性核损伤。

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