Che Xun, Liu Jinyi, Huang Haishan, Mi Xiaoyi, Xia Qing, Li Jingxia, Zhang Dongyun, Ke Qingdong, Gao Jimin, Huang Chuanshu
Nelson Institute of Environmental Medicine, New York University, School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
Biochim Biophys Acta. 2013 Sep;1833(9):2083-91. doi: 10.1016/j.bbamcr.2013.04.012. Epub 2013 Apr 29.
p27 is a cyclin-dependent kinase (CDK) inhibitor that suppresses a cell's transition from G0 to S phase, therefore acting as a tumor suppressor. Our most recent studies demonstrate that upon arsenite exposure, p27 suppresses Hsp27 and Hsp70 expressions through the JNK2/c-Jun- and HSF-1-dependent pathways, suggesting a novel molecular mechanism underlying the tumor suppressive function of p27 in a CDK-independent manner. We found that p27-deficiency (p27-/-) resulted in the elevation of cyclooxygenase-2 (COX-2) expression at transcriptional level, whereas the introduction of p27 brought back COX-2 expression to a level similar to that of p27+/+ cells, suggesting that p27 exhibits an inhibitory effect on COX-2 expression. Further studies identified that p27 inhibition of COX-2 expression was specifically due to phosphorylation of transcription factor cAMP response element binding (CREB) phosphorylation mediated by p38β and p38δ. These results demonstrate a novel mechanism underlying tumor suppression effect of p27 and will contribute to the understanding of the overall mechanism of p27 tumor suppression in a CDK-independent manner.
p27是一种细胞周期蛋白依赖性激酶（CDK）抑制剂，可抑制细胞从G0期向S期的转变，因此起到肿瘤抑制作用。我们最近的研究表明，暴露于亚砷酸盐后，p27通过JNK2/c-Jun和HSF-1依赖性途径抑制Hsp27和Hsp70的表达，提示p27以不依赖CDK的方式发挥肿瘤抑制功能的一种新分子机制。我们发现p27基因缺陷（p27-/-）导致转录水平上环氧合酶-2（COX-2）表达升高，而引入p27可使COX-2表达恢复到与p27+/+细胞相似的水平，表明p27对COX-2表达具有抑制作用。进一步研究发现，p27对COX-2表达的抑制作用具体是由于p38β和p38δ介导的转录因子cAMP反应元件结合蛋白（CREB）磷酸化所致。这些结果证明了p27肿瘤抑制作用的一种新机制，并将有助于以不依赖CDK的方式理解p27肿瘤抑制的整体机制。
