Ser/Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest
Ser/Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest
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DOI：
10.1021/bi990842e
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发表时间：
1999-07-13
期刊：
影响因子：
2.9
通讯作者：
Honkanen, RE
中科院分区：
文献类型：
--
作者：
Zuo, Z;Urban, G;Honkanen, RE
最近，配体诱导的糖皮质激素受体（GR）激活与通过 p21（WAF1/Cip1）转录诱导抑制细胞增殖有关，p21（WAF1/Cip1）是细胞周期蛋白依赖性蛋白激酶的通用抑制剂。在此，我们鉴定了一种 Ser/Thr 蛋白磷酸酶 (PP5)，它通过抑制糖皮质激素和 p53 介导的信号通路导致 p21(WAF1/Cip1) 介导的生长停滞来促进细胞增殖。抑制 PP5 表达 (1) 显着增加 GR 与其同源 DNA 结合序列的关联，(2) 在不添加激素的情况下诱导 GR 转录活性，(3) 将地塞米松介导的 GR 报告基因活性诱导增加到类似于 PP5 存在时可获得的最大响应高 10 倍的水平。 PP5 对激素与 GR 的结合没有明显影响，地塞米松介导的生长停滞与 p53 磷酸化的增加相关。对 p53 野生型、p53 缺陷型和 p53 缺陷型细胞系的比较研究表明，(1) p53 参与 GR 介导的 p21(WAF1/Cip1) 诱导，糖皮质激素诱导的基础 p53 过度磷酸化足以在 PP5 表达受到抑制时传播抗增殖反应，或 (2) PP5 在 p53 介导的情况下起作用GR诱导的信号网络汇聚来调节p21（WAF1/Cip1）的转录诱导。因此，异常的PP5表达可能对人类癌症的发展产生累加效应，通过抑制GR诱导的抗增殖信号级联反应促进细胞增殖，并通过抑制生长停滞的p53介导的反应来促进肿瘤转化，以防止基因组不稳定。
Ligand-induced glucocorticoid receptor (GR) activation has recently been linked to the inhibition of cell proliferation via the transcriptional induction of p21(WAF1/Cip1), which functions as a universal inhibitor of cyclin-dependent protein kinases. Herein, we identify a Ser/Thr protein phosphatase (PP5) that promotes cellular proliferation by inhibiting both glucocorticoid and p53-mediated signaling pathways leading to p21(WAF1/Cip1)-mediated growth arrest. The suppression of PP5 expression (1) markedly increases the association of GR with its cognate DNA-binding sequence, (2) induces GR transcriptional activity without the addition of hormone, and (3) increases dexamethasone-mediated induction of GR reporter activity to a level that is similar to 10 times greater than the maximal response obtainable in the presence of PP5. PP5 has no apparent effect on the binding of hormone to the GR, and dexamethasone-mediated growth arrest correlates with an increase in p53 phosphorylation. Comparative studies in p53-wild-type, p53-defective, and p53-deficient cell lines indicate that either (1) p53 participates in GR-mediated induction of p21(WAF1/Cip1), with the hyperphosphorylation of basal p53 induced by glucocorticoids sufficient for the propagation of an antiproliferative response when PP5 expression is inhibited, or (2) PP5 acts where p53-mediated and GR-induced signaling networks converge to regulate the transcriptional induction of p21(WAF1/Cip1). Thus, aberrant PP5 expression may have an additive effect on the development of human cancers by promoting cell proliferation via the inhibition of a GR-induced antiproliferative signaling cascade, and facilitating neoplastic transformation via the inhibition of a growth-arresting p53-mediated response that guards against genomic instability.