期刊
ONCOGENE
卷 22, 期 38, 页码 6023-6031出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1206875
关键词
historic deacetylase inhibitor; apicidin; p21(WAF1/Cip1); PI 3-kinase; PKC epsilon
We previously reported that the activation of p21(WAF1/Cip1) transcription by histone deacetylase inhibitor apicidin was mediated through Sp1 sites and pointed to the possible participation of protein kinase C (PKC). In this study, we investigated the role and identity of the specific isoforms of PKC involved and identified phosphatidylinositol 3-kinase (PI 3-kinase) as an upstream effector in HeLa cells. Using an isoform-specific pharmacological inhibitor of PKC, a PKCepsilon dominant-negative mutant, and antisense oligonucleotide to inhibit PKCepsilon specifically, we found that among PKC isoforms, PKCepsilon was required for the p21(WAF1/Cip1) expression by apicidin. In addition to PKCepsilon, PI 3-kinase appeared to participate in the activation of p21(WAF1/Cip1) promoter by apicidin, since inactivation of PI 3-kinase either by transient expression of dominant-negative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21(WAF1/Cip1) promoter and p21(WAF1/Cip1) protein expression by apicidin. Furthermore, membrane translocation of PKCepsilon in response to apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PRO: in the p21(WAF1/Cip1) promoter activation by apicidin. However, the p21(WAF1/Cip1) expression by apicidin appeared to be independent of the histone hyperacetylation, since apicidin-induced histone hyperacetylation of p21(WAF1/Cip1) promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21(WAF1/Cip1) by apicidin. Taken together, these results suggest that the PI 3-kinase-PKCepsilon signaling pathway plays a pivotal role in the expression of the p21(WAF1/Cip1) by apicidin.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据