Retinoblastoma protein-dependent growth signal conflict and caspase activity are required for protein kinase C-signaled apoptosis of prostate epithelial cells.
Retinoblastoma protein-dependent growth signal conflict and caspase activity are required for protein kinase C-signaled apoptosis of prostate epithelial cells.
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视网膜母细胞瘤蛋白依赖性生长信号冲突和 caspase 活性是蛋白激酶 C 信号的前列腺上皮细胞凋亡所必需的。
DOI：
10.1074/jbc.272.36.22751
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Day,ML
中科院分区：
文献类型：
--
作者：
Zhao,X;Gschwend,JE;Powell,CT;Foster,RG;Day,KC;Day,ML
蛋白激酶C和视网膜母细胞瘤肿瘤抑制蛋白都与细胞生长和细胞死亡的调节有关，表明这些因子在介导细胞命运中发挥不同的作用。在某些细胞中，蛋白激酶C诱导的视网膜母细胞瘤蛋白激活导致G1期阻滞。然而，在前列腺上皮细胞系LNCaP中，蛋白激酶Cα同工酶的诱导性过表达和激活或添加12-O-十四烷酰基佛波醇-13-乙酸酯导致凋亡，随后诱导p21和视网膜母细胞瘤蛋白的去磷酸化。与成视网膜细胞瘤生长抑制蛋白在蛋白激酶C诱导的细胞凋亡中的作用一致，不表达功能性成视网膜细胞瘤蛋白的DU 145细胞或已转染成视网膜细胞瘤抑制剂E1 a的LNCaP细胞对细胞凋亡具有抗性。LNCaP细胞凋亡是由视网膜母细胞瘤蛋白的生长抑制活性和生长促进有丝分裂信号之间的独特冲突引发的。因此，当这种冲突被血清耗竭阻止时，细胞凋亡被抑制。半胱氨酸蛋白酶的半胱天冬酶家族被认为包括哺乳动物细胞凋亡的执行机制，并且加入细胞可渗透的半胱天冬酶抑制剂Z-Val-Ala-Asp-氟甲基酮，提供了几乎完全的保护，免受蛋白激酶C信号细胞凋亡。这种保护与caspase活性的总损失相关，如通过核聚（ADP-核糖）聚合酶的蛋白水解裂解所测量的。在这些结果的基础上，我们提出，蛋白激酶C调节一种新的细胞死亡途径，这是由视网膜母细胞瘤生长抑制信号和血清促有丝分裂信号之间的细胞冲突，在增殖的前列腺上皮细胞，并执行半胱氨酸蛋白酶家族。
Both protein kinase C and the retinoblastoma tumor suppressor protein have been linked to the regulation of cell growth and cell death, suggesting the differential roles these factors play in mediating cell fate. In some cells, protein kinase C-induced activation of the retinoblastoma protein results in G1arrest. However, inducible overexpression and activation of the protein kinase Cα isozyme or the addition of 12-O-tetradecanoylphorbol-13-acetate in the prostate epithelial cell line, LNCaP, resulted in apoptosis preceded by induction of p21 and dephosphorylation of the retinoblastoma protein. Consistent with a role for the retinoblastoma growth suppressor protein in protein kinase C-induced apoptosis, DU145 cells, which do not express functional retinoblastoma protein or LNCaP cells, which have been transfected with the retinoblastoma inhibitor, E1a, were resistant to apoptosis. LNCaP apoptosis was initiated by a unique conflict between the growth-suppressive activity of the retinoblastoma protein and growth-promoting mitogenic signals. Thus, when this conflict was prevented by serum depletion, apoptosis was suppressed. The caspase family of cysteine proteases is believed to encompass the execution machinery of mammalian apoptosis, and addition of the cell-permeable caspase inhibitor, Z-Val-Ala-Asp-fluoromethylketone, afforded nearly total protection from protein kinase C-signaled apoptosis. This protection correlated with the total loss of caspase activity as measured by the proteolytic cleavage of nuclear poly(ADP-ribose) polymerase. On the basis of these results, we propose that protein kinase C regulates a novel cell death pathway that is initiated by a cellular conflict between retinoblastoma growth-suppressive signals and serum mitogenic signals in proliferating prostate epithelial cells and that is executed by the caspase family of cysteine proteases.