Mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma: role of p53-dependent and independent signal transduction pathways.
Mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma: role of p53-dependent and independent signal transduction pathways.
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发表时间：
1994-12
期刊：
影响因子：
8
通讯作者：
M. Sheikh;X. -. Li;J. Chen;Z. Shao;J. Ordonez;J. Fontana
中科院分区：
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作者：
M. Sheikh;X. -. Li;J. Chen;Z. Shao;J. Ordonez;J. Fontana
WAF1/Cip1是最近发现的野生型P53靶点，它似乎介导了P53的肿瘤抑制作用。本研究探讨了WAF1/Cip1基因在人乳腺癌细胞中表达的调控机制。我们的结果表明，携带野生型P53的HBC细胞表达的WAF1/Cip1mRNA水平是含有突变型P53的HBC细胞的26-33倍。DNA损伤剂依托泊苷只诱导野生型P53基因在野生型和突变型P53细胞中积聚，而在野生型和突变型P53细胞中诱导WAF1/Cip1基因表达，提示P53依赖和独立的信号通路参与了WAF1/Cip1基因表达的调控。血清饥饿诱导生长停滞，虽然不改变内源性P53水平或其反式激活报告基因的能力，但在携带野生型和突变型P53的细胞中诱导WAF1/Cip1基因表达。这些结果进一步表明，WAF1/Cip1基因调控可能涉及P53非依赖的信号转导通路。我们的数据还表明，在含有野生型或突变型p53的细胞中，WAF1/Cip1基因的表达与细胞周期进展密切相关。WAF1/Cip1的表达是瞬时诱导的，并随着细胞进入细胞周期的S期而下降。因此，我们提供的证据表明，WAF1/Cip1基因调控的机制涉及HBC中P53依赖和独立的信号通路。
WAF1/Cip1 was recently identified as the wild-type p53 target that appears to mediate the tumor suppressing effects of p53. We investigated the mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma (HBC) cells. Our results demonstrate that the HBC cells harboring wild-type p53 express 26-33-fold higher WAF1/Cip1 mRNA levels than the cells harboring mutant p53. The DNA damaging agent etoposide induced p53 accumulation only in cells harboring wild-type p53 yet it induced WAF1/Cip1 gene expression in cells carrying wild-type or mutant p53, suggesting the involvement of p53-dependent and independent signaling pathways in the regulation of WAF1/Cip1 gene expression. Serum starvation-induced growth arrest although not altering the endogenous p53 levels or its ability to transactivate the reporter gene, induced WAF1/Cip1 gene expression in cells carrying wild-type as well as mutant p53. These results further implicated the involvement of p53-independent signal transduction pathways in WAF1/Cip1 gene regulation. Our data also suggest that WAF1/Cip1 gene expression is tightly associated with cell cycle progression in cells containing either wild-type or mutant p53. WAF1/Cip1 expression was transiently induced in response to serum treatment and declined as the cells passed through the S-phase of the cell cycle. We thus provide evidence that the mechanisms of WAF1/Cip1 gene regulation involve p53-dependent and independent signaling pathways in HBC.