The PTEN tumor suppressor protein inhibits tumor necrosis factor-induced nuclear factor κB activity
The PTEN tumor suppressor protein inhibits tumor necrosis factor-induced nuclear factor κB activity
复制标题
DOI：
10.1074/jbc.m102559200
复制
发表时间：
2001-07-20
影响因子：
4.8
通讯作者：
Donner, DB
中科院分区：
文献类型：
--
作者：
Gustin, JA;Maehama, T;Donner, DB
核因子kappaB（NF-kappaB）转录激活促进免疫和细胞存活的基因。NF-κ B的激活由I κ B激酶（IKK）复合物诱导，所述IKK复合物磷酸化并促进I κ B从NF-κ B解离，然后NF-κ B易位到细胞核中。肿瘤坏死因子（TNF）激活磷脂酰肌醇（PI）3-激酶/Akt信号传导可激活IKK和NF-κ B。目前的研究表明，PTEN，一种抑制PI 3-激酶功能的肿瘤抑制因子，损害了293细胞中Akt和IKK复合物的TNF活化。瞬时表达的PTEN抑制IKK激活和TNF诱导的NF-κ B DNA结合和反式激活。用不表达PTEN的PC-3前列腺癌细胞和表达PTEN的DU 145前列腺癌细胞进行研究。TNF在PC-3细胞中激活Akt，但在DU 145细胞中不激活，并且TNF激活NF-κ B的能力在PC-3细胞中被PI 3-激酶活性的药理学抑制所阻断，但在DU 145细胞中不被阻断。PC-3细胞中PTEN的表达达到与DU 145细胞中内源性存在的水平相当的水平，抑制TNF对NF-κ B的活化。PTEN负调节PI 3-激酶/AKT/NF-κ B通路的细胞类型特异性能力可能对其肿瘤抑制活性很重要。
Nuclear factor kappaB (NF-kappaB) transcriptionally activates genes that promote immunity and cell survival. Activation of NF-kappaB is induced by an I kappaB kinase (IKK) complex that phosphorylates and promotes dissociation of I kappaB from NF-kappaB, which then translocates into the nucleus. Activation of phosphatidylinositol (PI) 3-kinase/Akt signaling by tumor necrosis factor (TNF) activates IKK and NF-kappaB. The present study shows that PTEN, a tumor suppressor that inhibits PI 3-kinase function, impairs TNF activation of Akt and the IKK complex in 293 cells. Transient expression of PTEN suppressed IKK activation and TNF-induced NF-kappaB DNA binding and transactivation. Studies were conducted with PC-3 prostate cancer cells that do not express PTEN and DU145 prostate cancer cells that express PTEN. TNF activated Akt in PC-3 cells, but not in DU145 cells, and the ability of TNF to activate NF-kappaB was blocked by pharmacological inhibition of PI 3-kinase activity in PC-3 cells, but not in DU145 cells. Expression of PTEN in PC-3 cells to a level comparable with that endogenously present in DU145 cells inhibited TNF activation of NF-kappaB. The cell type-specific ability of PTEN to negatively regulate the PI 3-kinase/AKT/NF-kappaB pathway may be important to its tumor suppressor activity.