12-O-tetradecanoylphorbol-13-acetate induces apoptosis in renal epithelial cells through a growth signal conflict which is prevented by activated ras.
12-O-tetradecanoylphorbol-13-acetate induces apoptosis in renal epithelial cells through a growth signal conflict which is prevented by activated ras.
复制标题
12-O-tetradecanoylphorbol-13-acetate 通过生长信号冲突诱导肾上皮细胞凋亡，而激活的 ras 可阻止生长信号冲突。
DOI：
10.1006/abbi.2000.2182
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发表时间：
2001
影响因子：
3.9
通讯作者：
Rosson,D
中科院分区：
文献类型：
--
作者：
Lee,RG;Rosson,D
通过caspase 3激活评估，12- o - tetradecanoylphorboll -13-acetate （TPA）在处理24 h后诱导猪肾上皮细胞株llc - pk1凋亡。与苔藓抑素共处理的细胞明显降低了TPA的凋亡作用。另一种肿瘤促进剂冈田酸也能诱导细胞凋亡。激活的ras基因的表达阻止了tpa诱导的细胞凋亡，而显性的阴性ras基因则延缓了这一过程。综上所述，这些结果表明，tpa诱导的llc - pk1细胞凋亡可能类似于tpa诱导的两阶段皮肤癌变模型中的肿瘤促进。从机制上讲，TPA诱导的细胞凋亡似乎是血清促生长作用和TPA抑制生长作用相互冲突的结果。这表现为视网膜母细胞瘤基因产物pRb的显著低磷酸化，这被激活的ras阻止。细胞凋亡和pRb低磷酸化与细胞周期蛋白D1水平降低相关，提示TPA通过调节该细胞周期蛋白产生生长阻滞作用。有趣的是，激活ras的保护机制似乎并不像其他系统中涉及的那样是由磷脂酰肌醇-3激酶（PI3K）的下游激活引起的。进一步的分析显示，tpa诱导的细胞凋亡与抗凋亡蛋白Bcl-x和Mcl-1的下调有关，并依赖于转录因子Jun的活性。
12-O-Tetradecanoylphorbol-13-acetate (TPA) induced apoptosis in the pig renal epithelial cell line LLC-PK1after 24 h of treatment as assessed by caspase 3 activation. Cotreatment of the cells with bryostatin markedly reduced the apoptotic effects of TPA. Okadaic acid, another tumor promoter, also induced apoptosis. Expression of an activated ras gene prevented TPA-induced apoptosis, while a dominant negative ras retarded the process. Taken together, these results suggest that TPA-induced apoptosis in LLC-PK1may be analogous to TPA-induced tumor promotion in the two-stage model of skin carcinogenesis. Mechanistically, TPA-induced apoptosis seemed to be the result of a conflict of the growth-promoting affects of serum and the growth-retarding effects of TPA. This was manifested by a pronounced hypophosphorylation of the retinoblastoma gene product, pRb, which was prevented by activated ras. Apoptosis and pRb hypophosphorylation were associated with a reduction in cyclin D1 levels, suggesting that the growth-retarding effects of TPA were produced by modulation of this cell cycle protein. Interestingly, the mechanism of protection by activated ras did not seem to result from downstream activation of phosphatidylinositol-3-kinase (PI3K) as has been implicated in other systems. Additional analysis revealed that TPA-induced apoptosis was associated with the downregulation of the anti-apoptotic proteins Bcl-x and Mcl-1 and dependent on the activity of the transcription factor Jun.