Protein Kinase A Regulates MYC Protein through Transcriptional and Post-translational Mechanisms in a Catalytic Subunit Isoform-specific Manner
Protein Kinase A Regulates MYC Protein through Transcriptional and Post-translational Mechanisms in a Catalytic Subunit Isoform-specific Manner
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DOI：
10.1074/jbc.m112.432377
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发表时间：
2013-05-17
影响因子：
4.8
通讯作者：
Bieberich, Charles J.
中科院分区：
文献类型：
--
作者：
Padmanabhan, Achuth;Li, Xiang;Bieberich, Charles J.
MYC水平在细胞中受到严格调控，而放松调控与许多癌症有关。在这份报告中，我们描述了细胞中存在一个MYC-蛋白激酶A(PKA)-Polo-like kinase1(PLK1)信号环。我们报道了PKA和PLK1连续的MYC磷酸化保护MYC免受蛋白酶体介导的降解。有趣的是，短期的PAN-PKA抑制降低了MYC的水平，而延长PKA催化亚基α(PKACα)的敲除，而不是PKA催化亚基β(PKACβ)的敲除，会增加MYC的水平。我们表明，PAN-PKA抑制对MYC的短期影响是翻译后的，而PKACα特异性的长期影响是转录的。这些数据还揭示了PKA催化亚型在MYC调控中的不同功能。我们将这种效应归因于PKA催化亚基之间不同的磷酸化选择性，我们在多个底物上证明了这一点。此外，我们还表明，MYC上调PKACβ，在转录上形成一个接近的正反馈环。这些结果确立了PKA作为MYC的调节因子，并突出了不同PKA催化亚基的不同生物学作用。
MYC levels are tightly regulated in cells, and deregulation is associated with many cancers. In this report, we describe the existence of a MYC-protein kinase A (PKA)-polo-like kinase 1 (PLK1) signaling loop in cells. We report that sequential MYC phosphorylation by PKA and PLK1 protects MYC from proteasome-mediated degradation. Interestingly, short term pan-PKA inhibition diminishes MYC level, whereas prolonged PKA catalytic subunit alpha (PKAC alpha) knockdown, but not PKA catalytic subunit beta (PKAC beta) knockdown, increases MYC. We show that the short term effect of pan-PKA inhibition on MYC is post-translational and the PKAC alpha-specific long term effect on MYC is transcriptional. These data also reveal distinct functional roles among PKA catalytic isoforms in MYC regulation. We attribute this effect to differential phosphorylation selectivity among PKA catalytic subunits, which we demonstrate for multiple substrates. Further, we also show that MYC up-regulates PKAC beta, transcriptionally forming a proximate positive feedback loop. These results establish PKA as a regulator of MYC and highlight the distinct biological roles of the different PKA catalytic subunits.