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 Mas
-
Proto-Oncogene Proteins c-myc / physiology*
-
Rats
-
Recombinant Fusion Proteins / physiology
-
Second Messenger Systems
-
Transcription, Genetic
Substances
-
Isoenzymes
-
MAS1 protein, human
-
Proto-Oncogene Mas
-
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