Lin D, Fiscella M, O'Connor P M, Jackman J, Chen M, Luo L L, Sala A, Travali S, Appella E, Mercer W E
Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19170.
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10079-83. doi: 10.1073/pnas.91.21.10079.
Overexpression of wild-type p53 protein has been shown to induce arrest in the G1 stage of the cell cycle and to transactivate expression of the gene that encodes the 21-kDa Waf1/Cip1 protein, a potent inhibitor of cyclin-dependent kinase activity. p53-dependent G1 arrest is accompanied by decreased expression of the B-myb gene, a relative of the c-myb cellular oncogene. In this study we show that B-myb expression is required for cells to progress from G1 into S phase and that high levels of ectopic B-myb expression uncoupled from cell cycle regulation rescues cells from p53-induced G1 arrest even in the presence of Waf1/Cip1 transactivation and inhibition of cyclin E/Cdk2 kinase activity. Cotransfection experiments with p53 expression plasmids and expression plasmids encoding in-frame deletion mutations in B-myb coding sequences indicate that the DNA-binding domain of the B-Myb protein is required for this activity. These results provide evidence of a bypass of p53-induced Waf1/Cip1-mediated cell cycle regulatory pathways by a member of the myb oncogene family.
野生型p53蛋白的过表达已被证明可诱导细胞周期G1期停滞，并反式激活编码21-kDa Waf1/Cip1蛋白的基因表达，该蛋白是细胞周期蛋白依赖性激酶活性的有效抑制剂。p53依赖的G1期停滞伴随着B-myb基因表达的降低，B-myb基因是c-myb细胞癌基因的一个亲属。在本研究中，我们表明B-myb表达是细胞从G1期进入S期所必需的，并且即使在存在Waf1/Cip1反式激活和细胞周期蛋白E/Cdk2激酶活性受到抑制的情况下，与细胞周期调控无关的高水平异位B-myb表达也能使细胞从p53诱导的G1期停滞中恢复。用p53表达质粒和编码B-myb编码序列框内缺失突变的表达质粒进行的共转染实验表明，B-Myb蛋白的DNA结合结构域是该活性所必需的。这些结果提供了证据，证明myb癌基因家族的一个成员可绕过p53诱导的Waf1/Cip1介导的细胞周期调控途径。
