Protein kinase A-dependent and -independent signaling pathways contribute to cyclic AMP-stimulated proliferation.
Protein kinase A-dependent and -independent signaling pathways contribute to cyclic AMP-stimulated proliferation.
复制标题
蛋白激酶 A 依赖性和非依赖性信号通路有助于环 AMP 刺激的增殖。
DOI：
10.1128/mcb.19.9.5882
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发表时间：
1999
影响因子：
5.3
通讯作者：
Meinkoth,JL
中科院分区：
文献类型：
--
作者：
Cass,LA;Summers,SA;Prendergast,GV;Backer,JM;Birnbaum,MJ;Meinkoth,JL
环AMP （cAMP）对细胞增殖的影响是细胞类型特异性的。尽管对cAMP的生长抑制作用已经有了很好的研究，但对cAMP如何刺激增殖知之甚少。我们报道了cAMP通过蛋白激酶A （PKA）依赖性和PKA非依赖性信号通路刺激增殖，并且磷脂酰肌醇3-激酶（PI3K）是cAMP刺激的有丝分裂发生所必需的。在cAMP为丝裂原的细胞中，cAMP升高剂刺激膜皱缩、Akt磷酸化和p70核糖体S6蛋白激酶（p70s6k）活性。cAMP对皱褶形成和Akt的影响与PKA无关，但对wortmannin敏感。相比之下，camp刺激的p70s6k活性被PKA抑制剂抑制，而wortmannin或微量注射PI3K的p85调节亚基的n端SH2结构域则不受抑制，这表明p70s6k和Akt可以独立调节。微量注射高度特异性的PI3K或Rac1抑制剂，或用p70s6k抑制剂雷帕霉素治疗，会损害camp刺激的DNA合成，这表明pka依赖性和非依赖性途径有助于camp介导的有丝分裂发生。当p70s6k活性升高时，通过微量注射刺激PI3K活性的抗体或膜定位p110的稳定表达直接升高PI3K活性，足以赋予激素非依赖性DNA合成。这些发现表明，camp刺激的有丝分裂发生有多种途径，其中只有一些是依赖于PKA的。此外，他们证明了cAMP刺激p70s6k和pi3k依赖通路的能力是cAMP调节细胞周期进程的一个重要方面。
The effects of cyclic AMP (cAMP) on cell proliferation are cell type specific. Although the growth-inhibitory effects of cAMP have been well studied, much less is known regarding how cAMP stimulates proliferation. We report that cAMP stimulates proliferation through both protein kinase A (PKA)-dependent and PKA-independent signaling pathways and that phosphatidylinositol 3-kinase (PI3K) is required for cAMP-stimulated mitogenesis. In cells where cAMP is a mitogen, cAMP-elevating agents stimulate membrane ruffling, Akt phosphorylation, and p70 ribosomal S6 protein kinase (p70s6k) activity. cAMP effects on ruffle formation and Akt were PKA independent but sensitive to wortmannin. In contrast, cAMP-stimulated p70s6k activity was repressed by PKA inhibitors but not by wortmannin or microinjection of the N-terminal SH2 domain of the p85 regulatory subunit of PI3K, indicating that p70s6k and Akt can be regulated independently. Microinjection of highly specific inhibitors of PI3K or Rac1, or treatment with the p70s6k inhibitor rapamycin, impaired cAMP-stimulated DNA synthesis, demonstrating that PKA-dependent and -independent pathways contribute to cAMP-mediated mitogenesis. Direct elevation of PI3K activity through microinjection of an antibody that stimulates PI3K activity or stable expression of membrane-localized p110 was sufficient to confer hormone-independent DNA synthesis when accompanied by elevations in p70s6k activity. These findings indicate that multiple pathways contribute to cAMP-stimulated mitogenesis, only some of which are PKA dependent. Furthermore, they demonstrate that the ability of cAMP to stimulate both p70s6k- and PI3K-dependent pathways is an important facet of cAMP-regulated cell cycle progression.