Induction of the Apoptosis Inhibitor ARC by Ras in Human Cancers*
Induction of the Apoptosis Inhibitor ARC by Ras in Human Cancers*
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DOI：
10.1074/jbc.m110.114892
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发表时间：
2010-04
期刊：
影响因子：
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通讯作者：
Lily Wu;Y. Nam;G. Kung;M. Crow;R. Kitsis
中科院分区：
文献类型：
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作者：
Lily Wu;Y. Nam;G. Kung;M. Crow;R. Kitsis
抑制细胞凋亡是肿瘤发生的关键。ARC(带有caspase募集结构域的凋亡抑制因子)是一种内源性的凋亡抑制因子，可以拮抗内源性和外源性的细胞凋亡途径。虽然ARC通常在横纹肌细胞和神经元中表达，但在各种原发人类上皮性癌症中显著诱导，并使癌细胞产生抗杀作用。在癌症中介导ARC诱导的机制尚不清楚。在这里，我们证明了ARC丰度的增加是由RAS通过影响转录和蛋白质稳定性来刺激的。激活的N-RAS或H-RAS在正常细胞中的过度表达足以增加ARC的mRNA和蛋白水平。同样，转基因表达活化的H-RAS在正常的乳腺上皮和由此产生的完整小鼠的肿瘤中都诱导了ARC。相反，乳腺癌和结肠癌细胞中内源性N-RAS的敲除显著降低了ARC的mRNA和蛋白水平。编码ARC的NOL3基因启动子被N-RAS和H-RAS以MEK/ERK依赖的方式激活。RAS还通过抑制ARC蛋白的多泛素化和随后的蛋白酶体降解来稳定ARC蛋白。除了RAS对ARC丰度的影响外，ARC还介导RAS诱导的细胞存活和细胞周期进程。因此，RAS在上皮性癌中诱导ARC，ARC在RAS的致癌作用中发挥作用。
Inhibition of apoptosis is critical for carcinogenesis. ARC (apoptosis repressor with caspase recruitment domain) is an endogenous inhibitor of apoptosis that antagonizes both intrinsic and extrinsic apoptosis pathways. Although normally expressed in striated myocytes and neurons, ARC is markedly induced in a variety of primary human epithelial cancers and renders cancer cells resistant to killing. The mechanisms that mediate the induction of ARC in cancer are unknown. Herein we demonstrate that increases in ARC abundance are stimulated by Ras through effects on transcription and protein stability. Overexpression of activated N-Ras or H-Ras in normal cells is sufficient to increase ARC mRNA and protein levels. Similarly, transgenic expression of activated H-Ras induces ARC in both the normal mammary epithelium and resulting tumors of intact mice. Conversely, knockdown of endogenous N-Ras in breast and colon cancer cells significantly reduces ARC mRNA and protein levels. The promoter of the Nol3 locus, encoding ARC, is activated by N-Ras and H-Ras in a MEK/ERK-dependent manner. Ras also stabilizes ARC protein by suppressing its polyubiquitination and subsequent proteasomal degradation. In addition to the effects of Ras on ARC abundance, ARC mediates Ras-induced cell survival and cell cycle progression. Thus, Ras induces ARC in epithelial cancers, and ARC plays a role in the oncogenic actions of Ras.