CONSTITUTIVE EXPRESSION OF B-MYB CAN BYPASS P53-INDUCED WAF1/CIP1-MEDIATED G(1) ARREST
CONSTITUTIVE EXPRESSION OF B-MYB CAN BYPASS P53-INDUCED WAF1/CIP1-MEDIATED G(1) ARREST
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DOI：
10.1073/pnas.91.21.10079
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发表时间：
1994-10-11
影响因子：
11.1
通讯作者：
MERCER, WE
中科院分区：
文献类型：
--
作者：
LIN, D;FISCELLA, M;MERCER, WE
野生型p53蛋白的过表达可诱导细胞周期G（1）期阻滞，并反式激活编码21-kDa Waf 1/Cip 1蛋白的基因的表达，Waf 1/Cip 1蛋白是细胞周期蛋白依赖性激酶活性的有效抑制剂。p53依赖性G（1）期阻滞伴随着B-myb基因表达的降低，B-myb基因是c-myb细胞癌基因的一种相关基因。在这项研究中，我们发现B-myb表达是细胞从G（1）期进入S期所必需的，并且即使在Waf 1/Cip 1反式激活和细胞周期蛋白E/Cdk 2激酶活性抑制的情况下，与细胞周期调控不偶联的高水平异位B-myb表达也能拯救细胞免于p53诱导的G（1）期阻滞。用p53表达质粒和编码B-myb编码序列中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的旁路p53诱导的Waf 1/Cip 1介导的细胞周期调控途径的myb癌基因家族的成员。
Overexpression of wild-type p53 protein has been shown to induce arrest ih the G(1) 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 G(1) 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 G(1) into S phase and that high levels of ectopic B-myb expression uncoupled from cell cycle regulation rescues cells from p53-induced G(1) 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.