Zhang Jin, Jun Cho Seong, Chen Xinbin
Comparative Cancer Center, University of California, Davis, CA 95616, USA.
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9614-9. doi: 10.1073/pnas.0912594107. Epub 2010 May 10.
P63, a p53 family tumor suppressor, is involved in many cellular processes, including growth suppression and differentiation. Thus, p63 activity needs to be tightly controlled. Here, we found that RNPC1, a RNA-binding protein and a target of the p53 family, regulates p63 mRNA stability and consequently p63 activity. Specifically, we showed that overexpression of RNPC1 decreases, whereas knockdown of RNPC1 increases, the half-life of p63 transcript, which leads to altered p63 expression. Consistent with this, we showed that RNPC1 binds the AU-/U-rich elements in p63 3' UTR in vitro and in vivo and the RRM domain in RNPC1 is required for binding, and regulating the stability of, p63 transcript. Furthermore, we showed that RNPC1 promotes keratinocyte differentiation by repressing p63 expression. Together, we uncovered a previously undetected mechanism by which p63 expression is regulated via mRNA stability and a novel regulatory feedback loop between RNPC1 and p63.
p63是一种p53家族的肿瘤抑制因子，参与包括生长抑制和分化在内的许多细胞过程。因此，p63的活性需要受到严格控制。在此，我们发现RNA结合蛋白RNPC1作为p53家族的一个靶点，可调节p63 mRNA的稳定性，进而调控p63的活性。具体而言，我们发现RNPC1的过表达会缩短p63转录本的半衰期，而敲低RNPC1则会延长其半衰期，这导致p63表达发生改变。与此一致的是，我们发现RNPC1在体外和体内均能与p63 3'UTR中的富含AU/ U的元件结合，且RNPC1中的RRM结构域是结合及调控p63转录本稳定性所必需的。此外，我们还发现RNPC1通过抑制p63表达促进角质形成细胞分化。总之，我们揭示了一种此前未被发现的通过mRNA稳定性调控p63表达的机制，以及RNPC1与p63之间新的调控反馈环路。
