PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells
PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells
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DOI：
10.1099/0022-1317-83-7-1651
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发表时间：
2002-07-01
影响因子：
3.8
通讯作者：
Steinberg, BM
中科院分区：
文献类型：
--
作者：
Sun, S;Steinberg, BM
喉乳头状瘤是由人乳头瘤病毒6型或11型（HPV-6/-11）感染喉上皮引起的。我们实验室之前的研究表明，乳头状瘤组织中 P13 激酶水平有所增加。然而，P13 激酶下游效应器蛋白激酶 B (PKB/Akt) 的激活减少。这一观察结果可以通过乳头状瘤组织中磷酸酶和张力蛋白同源物 (PTEN) 的表达升高来解释，PTEN 是一种最近鉴定的肿瘤抑制因子。最近对 PTEN 在乳头状瘤发育过程中可能的功能作用的研究表明，酪氨酸 (705) 磷酸化信号转导器和转录激活剂 3 [PTyr(705)STAT3] 的水平也可能与 PTEN 呈负相关。体外磷酸酶测定表明乳头状瘤提取物中 PTyr(705)STAT3 磷酸酶水平升高。乳头状瘤提取物中 PTEN 的免疫耗竭导致 PTyr(705)STAT3 磷酸酶活性降低。将 PTEN cDNA 转染 HeLa 细胞会以剂量依赖性方式减弱 Tyr(705) 上 STAT3 的磷酸化。 STAT3 磷酸化的这种减弱与 STAT3 激酶无关。有趣的是，相对于野生型 PTEN 转染获得的活性，引入 PTEN 脂质磷酸酶突变体 (G129E) 导致 PTyr(705)STAT3 磷酸酶活性增强。这些数据表明 PTEN 负向调节 HPV 感染的乳头状瘤细胞中 STAT3 的激活。 PTEN 的诱导和活化的 STAT3 的减少可能是宿主防御机制或病毒引导的改变正常上皮分化程序的策略的结果。
Laryngeal papillomas are caused by infection of the laryngeal epithelium by human papillomavirus type 6 or type 11 (HPV-6/-11). Previous studies in our laboratory have demonstrated an increase in P13 kinase levels in papilloma tissue. However, activation of the downstream effector of P13 kinase, protein kinase B (PKB/Akt), was reduced. This observation was explained by the elevated expression of the phosphatase and tensin homologue (PTEN), a recently characterized tumour suppressor, in papilloma tissue. Recent investigation of the possible functional roles of PTEN during papilloma development has now indicated that the level of tyrosine(705)-phosphorylated signal transducer and activator of transcription 3 [PTyr(705)STAT3] could be inversely correlated to that of PTEN as well. In vitro phosphatase assays suggested the presence of an increased level of a PTyr(705)STAT3 phosphatase in papilloma extract. Immunodepletion of PTEN from papilloma extracts resulted in a reduction of the PTyr(705)STAT3 phosphatase activity. Transfection of PTEN cDNA into HeLa cells attenuated STAT3 phosphorylation at Tyr(705) in a dose-dependent manner. This attenuation of STAT3 phosphorylation was independent of the STAT3 kinase. Interestingly, introduction of a lipid phosphatase mutant of PTEN (G129E) resulted in heightened PTyr(705)STAT3 phosphatase activity, relative to that obtained from wild-type PTEN transfection. These data indicate that PTEN negatively regulates STAT3 activation in HPV-infected papilloma cells. Induction of PTEN and reduction of activated STAT3 might be a result of a host defence mechanism or a virus-directed strategy to alter normal epithelial differentiation programming.