c-MYC Activates Protein Kinase A (PKA) by Direct Transcriptional Activation of the PKA Catalytic Subunit Beta (PKA-Cbeta) Gene

Oncogene. 2002 Nov 7;21(51):7872-82. doi: 10.1038/sj.onc.1205986.

Abstract

The c-MYC proto-oncogene encodes a ubiquitous transcription factor involved in the control of cell growth and differentiation and broadly implicated in tumorigenesis. Understanding the function of c-MYC and its role in cancer depends upon the identification of c-MYC target genes. Here we show that c-MYC induces the activity of Protein Kinase A (PKA), a key effector of cAMP-mediated signal transduction, by inducing the transcription of the gene encoding the PKA catalytic subunit beta (PKA-Cbeta). c-MYC-mediated induction of PKA-Cbeta gene transcription occurs in multiple tissues, is independent of cell proliferation and is mediated by direct binding of c-MYC to the PKA-Cbeta gene promoter sequences. Constitutive expression of PKA-Cbeta in Rat1A cells induces their transformation, and c-MYC-induced transformation can be reverted by pharmacological inhibition of PKA, suggesting that up-regulation of PKA is critical for c-MYC-associated tumorigenesis. These results indicate that, by activating PKA, c-MYC can provide endogenous activation of the cAMP signal transduction pathway independently of extracellular signals.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Cell Division
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic / genetics
  • Cyclic AMP / physiology
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / chemistry
  • Cyclic AMP-Dependent Protein Kinases / genetics*
  • Enzyme Induction
  • Fibroblasts / pathology
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Isoenzymes / genetics*
  • Luciferases / biosynthesis
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Organ Specificity
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / physiology*
  • Rats
  • Recombinant Fusion Proteins / physiology
  • Second Messenger Systems
  • Transcription, Genetic

Substances

  • Isoenzymes
  • Proto-Oncogene Proteins c-myc
  • Recombinant Fusion Proteins
  • Cyclic AMP
  • Luciferases
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • Cyclic AMP-Dependent Protein Kinases
  • protein kinase A Calpha