Jade-1, a candidate renal tumor suppressor that promotes apoptosis
Jade-1, a candidate renal tumor suppressor that promotes apoptosis
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DOI：
10.1073/pnas.0500757102
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发表时间：
2005-08-02
影响因子：
11.1
通讯作者：
Cohen, HT
中科院分区：
文献类型：
--
作者：
Zhou, MI;Foy, RL;Cohen, HT
晚期肾癌缺乏药物治疗，因此非常需要了解其发病机制。大多数肾癌的 von Hippel-Lindau 肿瘤抑制基因 pVHL 存在缺陷。 pVHL 蛋白抑制肾肿瘤的机制尚不清楚。 Jacle-1 是一种短寿命、富含肾脏的转录因子，通过与 pVHL 直接相互作用而稳定。 pVHL 导致的 Jade-1 稳定性丧失与肾癌风险相关，这使得 Jacle-1 与肾癌之间的关系引人注目。我们报告说，无论 VHL 状态如何，在所有测试的肾癌细胞系中几乎检测不到 Jade-1 表达。引人注目的是，蛋白酶体抑制剂处理使内源性 Jade-1 表达增加了 10 倍。 Jacle-1 抑制裸鼠肾癌细胞生长、集落形成和肿瘤形成。有趣的是，Jacle-1 还影响单层培养和 3D 培养中的细胞生长模式。 Jade-1 使细胞凋亡增加 40-50%，并降低抗细胞凋亡 Bcl-2 的水平。表达反义 Jade-1 的细胞证实了这些结果。因此，Jade-1 可能部分通过增加细胞凋亡来抑制肾癌细胞生长。 Jacle-1 可能代表肾癌中通常必须克服的促凋亡屏障，可能最初通过 pVHL 失活，随后通过增加蛋白酶体活性来克服。因此，Jade-1可能是一种肾肿瘤抑制剂。
Medical therapies are lacking for advanced renal cancer, so there is a great need to understand its pathogenesis. Most renal cancers have defects in the von Hippel-Lindau tumor suppressor pVHL. The mechanism by which pVHL protein functions in renal tumor suppression remains unclear. Jacle-1 is a short-lived, kidney-enriched transcription factor that is stabilized by direct interaction with pVHL. Loss of Jade-1 stabilization by pVHL correlates with renal cancer risk, making the relationship between Jacle-1 and renal cancer compelling. We report that Jade-1 expression was barely detectable in all tested renal cancer cell lines, regardless of VHL status. Strikingly, proteasome inhibitor treatment increased endogenous Jade-1 expression up to 10-fold. Jacle-1 inhibited renal cancer cell growth, colony formation, and tumor formation in nude mice. Intriguingly, Jacle-1 also affected the pattern of cell growth in monolayer culture and 3D culture. Jade-1 increased apoptosis by 40-50% and decreased levels of antiapoptotic Bcl-2. Antisense Jade-1-expressing cells confirmed these results. Therefore, Jade-1 may suppress renal cancer cell growth in part by increasing apoptosis. Jacle-1 may represent a proapoptotic barrier to proliferation that must be overcome generally in renal cancer, perhaps initially by pVHL inactivation and subsequently by increased proteasomal activity. Therefore, Jade-1 may be a renal tumor suppressor.