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首页> 外文期刊>Molecular and Cellular Biology >Protein Kinase A-Dependent and -Independent Signaling Pathways Contribute to Cyclic AMP-Stimulated Proliferation
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Protein Kinase A-Dependent and -Independent Signaling Pathways Contribute to Cyclic AMP-Stimulated Proliferation

机译：蛋白激酶A依赖和独立的信号通路有助于循环AMP刺激的增殖。

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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.
机译：环状AMP（cAMP）对细胞增殖的影响是细胞类型特异性的。尽管已经对cAMP的生长抑制作用进行了深入研究，但关于cAMP如何刺激增殖的了解还很少。我们报告cAMP刺激通过蛋白激酶A（PKA）依赖和PKA独立的信号通路的增殖，而磷脂酰肌醇3激酶（PI3K）是cAMP刺激的有丝分裂所必需的。在其中cAMP是有丝分裂原的细胞中，cAMP升高剂刺激膜起皱，Akt磷酸化和p70核糖体S6蛋白激酶（p70s6k）活性。 cAMP对褶皱形成和Akt的影响与PKA无关，但对渥曼青霉素敏感。相反，PKA抑制剂可抑制cAMP刺激的p70s6k活性，而渥曼青霉素或显微注射PI3K p85调节亚基的N末端SH2结构域则不能抑制cAMP刺激的p70s6k活性，这表明p70s6k和Akt可以独立调节。显微注射PI3K或Rac1的高度特异性抑制剂，或用p70s6k抑制剂雷帕霉素治疗，会损害cAMP刺激的DNA合成，表明PKA依赖性和非依赖性途径有助于cAMP介导的有丝分裂。通过微注射刺激PI3K活性的抗体或膜定位的p110的稳定表达，直接注射PI3K活性足以伴随p70s6k活性的升高而赋予激素非依赖性DNA合成。这些发现表明，多种途径有助于cAMP刺激的有丝分裂发生，其中只有一些是PKA依赖性的。此外，他们证明了cAMP刺激依赖p70s6k和PI3K通路的能力是cAMP调控细胞周期进程的重要方面。

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