NDLI: Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma

Content Provider	PubMed Central
Author	Zeng, Liling Bai, Ming Mittal, Amit K. El-jouni, Wassim Zhou, Jing Cohen, David M. Zhou, Mina I. Cohen, Herbert T.
Abstract	The von Hippel-Lindau tumor suppressor pVHL (VHL) is lost in the majority of clear-cell renal cell carcinomas (RCCs). Activation of the PI3K/AKT/mTOR pathway is also common in RCC, with PTEN loss occurring in ~30% of the cases, but other mechanisms responsible for activating AKT at a wider level in this setting are undefined. Plant homeodomain protein Jade-1 (PHF17) is a candidate renal tumor suppressor stabilized by pVHL. Here using kinase arrays we identified phospho-AKT1 as an important target of Jade-1. Overexpressing or silencing Jade-1 in RCC cells increased or decreased levels of endogenous phospho-AKT/AKT1. Further, reintroducing pVHL into RCC cells increased endogenous Jade-1 and suppressed endogenous levels of phospho-AKT, which colocalized with and bound to Jade-1. The N-terminus of Jade-1 bound both the catalytic domain and the C-terminal regulatory tail of AKT, suggesting a mechanism through which Jade-1 inhibited AKT kinase activity. Intriguingly, RCC precursor cells where Jade-1 was silenced exhibited an increased capacity for AKT-dependent anchorage-independent growth, in support of a tumor suppressor function for Jade-1 in RCC. In support of this concept, an in silico expression analysis suggested that reduced Jade-1 expression is a poor prognostic factor in clear-cell RCC that is associated with activation of an AKT1 target gene signature. Taken together, our results identify two mechanisms for Jade-1 fine control of AKT/AKT1 in RCC, through loss of pVHL, which decreases Jade-1 protein, or through attenuation in Jade-1 expression. These findings help explain the pathologic cooperativity in clear-cell RCC between PTEN inactivation and pVHL loss, which leads to decreased Jade-1 levels that superactivate AKT. Additionally, they prompt further investigation of Jade-1 as a candidate biomarker and tumor suppressor in clear-cell RCC.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-12-4707
Ending Page	5380
Page Count	10
Starting Page	5371
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	17
Volume Number	73
Language	English
Publisher Date	2013-09-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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