Abstract
The Zinc Finger (ZNF) 280B protein was identified as an unexpected target of an shRNA designed for sGCα1. Further analysis showed that these two proteins are connected in another way, with 280B up-regulation of sGCα1 expression. Knock-down and over-expression experiments showed that 280B serves pro-growth and pro-survival functions in prostate cancer. Surprisingly however, these pro-cancer functions of 280B are not mediated by sGCα1, which itself has similar functions in prostate cancer, but by down-regulated p53. The p53 protein is a second target of 280B in prostate cancer, but unlike sGCα1, p53 is down-regulated by 280B. 280B induces p53 nuclear export, leading to subsequent proteasomal degradation. The protein responsible for p53 regulation by 280B is Mdm2, the E3 ubiquitin ligase that promotes p53 degradation by inducing its nuclear export. We show here that 280B up-regulates expression of Mdm2 in prostate cancer cells, and this regulation is via the Mdm2 promoter. To demonstrate an in vivo relevance to this interaction, expression studies show that 280B protein levels are up-regulated in prostate cancer and these levels correspond to reduced levels of p53. Thus, by enhancing the expression of Mdm2, the uncharacterized 280B protein provides a novel mechanism of p53 suppression in prostate cancer.
Highlights
The p53 tumor suppressor has a pivotal role in coordinating cellular responses to various stresses [1]
We have previously reported that the a1 subunit of SGC is a direct target of androgen receptor (AR) and plays important role in driving prostate cancer cell proliferation [19]
An sGCa1 siRNA targets 280B in prostate cancer cells To study the role of endogenous sGCa1 in prostate cancer cells, we used shRNA to knockdown this gene in LNCaP cells
Summary
The p53 tumor suppressor has a pivotal role in coordinating cellular responses to various stresses (including DNA damage, over-expressed oncogenes and diverse metabolic limitations) [1]. It was later determined that a combined loss of p53 and PTEN, a tumor suppressor involved in PI3-AKT signaling [15], was sufficient to drive development of invasive prostate cancer [16]. Another tumor suppressor, NKX3.1, was shown to increase acetylation and stability of p53 via Mdm2-dependent mechanisms [17]
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