c-MYC activates protein kinase A (PKA) by direct transcriptional activation of the PKA catalytic subunit beta (PKA-Cbeta) gene

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.