Mitchell K O, El-Deiry W S
Howard Hughes Medical Institute, Department of Medicine, Cancer Center, and Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Cell Growth Differ. 1999 Apr;10(4):223-30.
The c-Myc oncoprotein is a transcription factor involved in cellular transformation. We previously found (M. V. Blagosklonny, et al., Cancer Res., 57: 320-325, 1997) that exposure of human SkBr3 breast cancer and LNCaP prostate cancer cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) led to a growth arrest associated with the up-regulation of the cyclin-dependent kinase inhibitor p21(WAF1/cIP1) and the inhibition of c-Myc expression. We show here that exogenous c-Myc inhibits p21 expression in SkBr3 and LNCaP cells induced to enter into S-phase. p27 expression was not increased from basal levels in TPA-treated growth-arrested cells. A time course after infection of TPA-arrested cells using a c-Myc-expressing adenovirus revealed that the inhibition of p21 expression preceded entry into S-phase. In contrast, after infection by E2F-1-expressing adenovirus, p21 expression was reduced after the cells entered S-phase. Overexpression of c-Myc reduced the levels of endogenous p21 mRNA, and transfection of c-Myc repressed p21-promoter luciferase-reporter gene expression. The results suggest that the down-regulation of p21 expression may contribute to c-Myc-dependent entry into S-phase, possibly in situations in which growth arrest is associated with increased p21 expression.
c-Myc癌蛋白是一种参与细胞转化的转录因子。我们之前发现（M. V. 布拉戈克隆尼等人，《癌症研究》，57: 320 - 325，1997），将人SkBr3乳腺癌细胞和LNCaP前列腺癌细胞暴露于12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）会导致生长停滞，这与细胞周期蛋白依赖性激酶抑制剂p21（WAF1/cIP1）的上调以及c-Myc表达的抑制有关。我们在此表明，外源性c-Myc抑制诱导进入S期的SkBr3和LNCaP细胞中p21的表达。在TPA处理的生长停滞细胞中，p27表达并未从基础水平增加。使用表达c-Myc的腺病毒感染TPA停滞细胞后的时间进程显示，p21表达的抑制先于进入S期。相反，在用表达E2F-1的腺病毒感染后，细胞进入S期后p21表达降低。c-Myc的过表达降低了内源性p21 mRNA的水平，并且c-Myc的转染抑制了p21启动子荧光素酶报告基因的表达。结果表明，p21表达的下调可能有助于c-Myc依赖性进入S期，可能是在生长停滞与p21表达增加相关的情况下。
