title: Protein kinase A regulates MYC protein through transcriptional and post-translational mechanisms in a catalytic subunit isoform-specific manner.
abstract: 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 α (PKACα) knockdown, but not PKA catalytic subunit β (PKACβ) knockdown, increases MYC. We show that the short term effect of pan-PKA inhibition on MYC is post-translational and the PKACα-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 PKACβ, 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.
authors.affiliation: Department of Biological Sciences, the University of Maryland Baltimore County, Baltimore, Maryland 21250.
authors.forename: Achuth
authors.initials: A
authors.lastname: Padmanabhan
authors.affiliation: Department of Biological Sciences, the University of Maryland Baltimore County, Baltimore, Maryland 21250.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, the University of Maryland Baltimore County, Baltimore, Maryland 21250; Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201. Electronic address: bieberic@umbc.edu.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Bieberich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D000097869:Polo-Like Kinase 1
keywords: Cancer Biology; MYC; Phosphorylation; Polo-like Kinase 1 (PLK1); Post-translational Modification; Protein Kinase A (PKA)