The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells
The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells
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DOI：
10.1074/jbc.271.2.901
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发表时间：
1996-01-12
影响因子：
4.8
通讯作者：
Kraft, AS
中科院分区：
文献类型：
--
作者：
Biggs, JR;Kudlow, JE;Kraft, AS
Waf1 / Cip1蛋白诱导细胞周期阻滞通过抑制细胞周期蛋白依赖性激酶的活性和增殖细胞核抗原,Waf1 / Cip1表达基因诱导p53-dependent的方式应对DNA损伤,但也可以在缺乏p53诱导代理人如生长因子、佛波醇酯,冈田酸,Waf1 / Cip1表达在人类白血病U937细胞是由佛波醇酯,蛋白激酶C的激活,冈田酸,一种磷酸酶1和2A的抑制剂，这两种药物都能诱导这些白血病细胞向巨噬细胞分化。研究表明，在U937细胞中，磷酯和冈田酸刺激WAF1/CIP1启动子的转录，这种转录是由启动子-154和+16之间的区域介导的，该区域包含转录因子Sp1的两个结合位点，这些Sp1位点的缺失或突变会降低WAF1/CIP1启动子对磷酯和冈田酸的响应。在Sp1缺失的果蝇SL细胞系中，外源Sp1也能高度诱导WAF1/CIP1启动子。这些结果表明，phorbol酯和okadaic酸通过包括Sp1和基础转录因子的蛋白复合物激活WAF1/CIP1启动子的转录。
The Waf1/Cip1 protein induces cell cycle arrest through inhibition of the activity of cyclin-dependent kinases and proliferating cell nuclear antigen, Expression of the WAF1/CIP1 gene is induced in a p53-dependent manner in response to DNA damage but can also be induced in the absence of p53 by agents such as growth factors, phorbol esters, and okadaic acid, WAF1/CIP1 expression in U937 human leukemic cells is induced by both phorbol ester, a protein kinase C activator, and by okadaic acid, an inhibitor of phosphatases 1 and 2A, Both of these agents induce the differentiation of these leukemic cells toward macrophages. We demonstrate that phorbol esters and okadaic acid stimulate transcription from the WAF1/CIP1 promoter in U937 cells, This transcription is mediated by a region of the promoter between -154 and +16, which contains two binding sites for the transcription factor Sp1, Deletion or mutation of these Sp1 sites reduces WAF1/CIP1 promoter response to phorbol ester and okadaic acid, while a reporter gene under the control of a promoter containing only multiple Sp1 binding sites and a TATA box is induced by phorbol ester and okadaic acid, The WAF1/CIP1 promoter is also highly induced by exogenous Sp1 in the Sp1-deficient Drosophila Schnieder SL 2 cell line, These results suggest that phorbol ester and okadaic acid activate transcription of the WAF1/CIP1 promoter through a complex of proteins that includes Spl and basal transcription factors.