Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells.
Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells.
复制标题
DOI：
10.1016/j.canlet.2015.08.012
复制
发表时间：
2015-12-01
期刊：
影响因子：
9.7
通讯作者：
Murph MM
中科院分区：
文献类型：
--
作者：
Altman MK;Alshamrani AA;Jia W;Nguyen HT;Fambrough JM;Tran SK;Patel MB;Hoseinzadeh P;Beedle AM;Murph MM
G 蛋白信号传导调节蛋白 10 (RGS10) 蛋白是一种 GTP 酶激活蛋白，可加速 GTP 的水解，从而典型地使 G 蛋白失活，最终终止信号传导。 Rheb 是一种小型 GTP 酶蛋白，可在 GDP 结合形式和 GTP 结合形式之间穿梭以激活 mTOR。由于 RGS10 抑制会增强卵巢癌细胞的活力，因此我们试图阐明其分子机制。在无血清条件下抑制 RGS10 后，mTOR、真核翻译起始因子 4E 结合蛋白 1 (4E-BP1)、p70S6K 和 S6 核糖体蛋白出现磷酸化。此外，抑制 RGS10 会增加激活的 Rheb，表明 RGS10 通过小 G 蛋白拮抗 mTOR 信号传导。使用生长因子、溶血磷脂酸刺激细胞后，RGS10 抑制的效果会增强，而使用 mTOR 抑制剂、替西罗莫司和 INK-128 则会减弱。即使存在依托泊苷，RGS10 的抑制也会导致细胞增殖增加。总之，RGS10 抑制会增加卵巢癌细胞中的 Rheb-GTP 和 mTOR 信号传导。我们的结果表明，RGS10 可以通过加速卵巢癌细胞中 Rheb 的 GTP 水解来发挥一种以前未知的新作用。
The regulator of G protein signaling 10 (RGS10) protein is a GTPase activating protein that accelerates the hydrolysis of GTP and therefore canonically inactivates G proteins, ultimately terminating signaling. Rheb is a small GTPase protein that shuttles between its GDP- and GTP-bound forms to activate mTOR. Since RGS10 suppression augments ovarian cancer cell viability, we sought to elucidate the molecular mechanism. Following RGS10 suppression in serum-free conditions, phosphorylation of mTOR, the eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), p70S6K and S6 Ribosomal Protein appear. Furthermore, suppressing RGS10 increases activated Rheb, suggesting RGS10 antagonizes mTOR signaling via the small G-protein. The effects of RGS10 suppression are enhanced after stimulating cells with the growth factor, lysophosphatidic acid, and reduced with mTOR inhibitors, temsirolimus and INK-128. Suppression of RGS10 leads to an increase in cell proliferation, even in the presence of etoposide. In summary, the RGS10 suppression increases Rheb-GTP and mTOR signaling in ovarian cancer cells. Our results suggest that RGS10 could serve in a novel, and previously unknown, role by accelerating the hydrolysis of GTP from Rheb in ovarian cancer cells.