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首页> 外文期刊>Cell Research >Anti-apoptotic effect of retinoic acid on retinal progenitor cells mediated by a protein kinase A-dependent mechanism
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Anti-apoptotic effect of retinoic acid on retinal progenitor cells mediated by a protein kinase A-dependent mechanism

机译：维甲酸对蛋白激酶A依赖机制介导的视网膜祖细胞的抗凋亡作用

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摘要

Retinal progenitor cells (RPCs) are neural stem cells able to differentiate into any normal adult retinal cell type, except for pigment epithelial cells. Retinoic acid (RA) is a powerful growth/differentiation factor that generally causes growth inhibition, differentiation and/or apoptosis. In this study, we demonstrate that RA not only affects mouse RPC differentiation but also improves cell survival by reducing spontaneous apoptotic rate without affecting RPC proliferation. The enhanced cell survival was accompanied by a significant upregulation of the expression of protein kinase A (PKA) and several protein kinase C (PKC) isoforms. Treatment of cells grown in RA-free media with 8-bromoadenosine3′,5′-cyclic monophosphate, a known activator of PKA, resulted in an anti-apoptotic effect similar to that caused by RA; whereas the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesul-fonamide dihydrochloride led to a significant (～32%) increase in apoptosis. In contrast, treatment of RPCs with any of two PKC selective inhibitors, 2,2′,3,3′,4,4′-hexahydroxy-1,1′-biphenyl-6,6′-dimethanol dimethyl ether and bisindolylmaleimide XI, led to diminished apoptosis; while a PKC activator, phorbol 12-myristate 13-acetate, increased apoptosis. These and other data suggest that the effect of RA on RPC survival is mostly due to the increased anti-apoptotic activity elicited by PKA, which might in turn be antagonized by PKC. Such a mechanism is a new example of tight regulation of important biological processes triggered by RA. Although the detailed mechanisms remain to be elucidated, we provide evidence that the pro-survival effect of RA on RPCs is not mediated by changed expression of p53 or bcl-2, and appears to be independent of β-amyloid, Fas ligand, TNF-α, ganglioside GM1 and ceramide C16-induced apoptotic pathways.
机译：视网膜祖细胞（RPCs）是神经干细胞，能够分化为任何正常的成年视网膜细胞类型，但色素上皮细胞除外。维甲酸（RA）是一种强大的生长/分化因子，通常会导致生长抑制，分化和/或凋亡。在这项研究中，我们证明RA不仅影响小鼠RPC分化，而且通过降低自发凋亡率而不影响RPC增殖来提高细胞存活率。细胞存活率的提高伴随着蛋白激酶A（PKA）和几种蛋白激酶C（PKC）同工型表达的显着上调。用8-溴腺苷3'，5'-环一磷酸酯（一种已知的PKA激活剂）处理无RA培养基中生长的细胞，其产生的抗凋亡作用与RA相似。而PKA抑制剂N- [2-（对溴肉桂酸氨基）乙基] -5-异喹啉基-甲酰胺二盐酸盐导致细胞凋亡显着增加（〜32％）。相比之下，用两种PKC选择性抑制剂（2,2'，3,3'，4,4'-六羟基-1,1'-联苯-6,6'-二甲醇二甲醚和双吲哚基马来酰亚胺XI）中的任何一种处理RPC，导致凋亡减少；而PKC激活剂佛波醇12-肉豆蔻酸酯13-乙酸酯则增加了细胞凋亡。这些和其他数据表明，RA对RPC存活的影响主要是由于PKA引起的抗凋亡活性增加，而PKC可能反过来。这种机制是严格调控由RA触发的重要生物过程的新例子。尽管尚需阐明详细的机制，但我们提供的证据表明RA对RPC的促生存作用不受p53或bcl-2表达变化的介导，并且似乎独立于β淀粉样蛋白，Fas配体，TNF-α α，神经节苷脂GM1和神经酰胺C16诱导的凋亡途径。

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