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 β (PKA-Cβ). c-MYC-mediated induction of PKA-Cβ gene transcription occurs in multiple tissues, is independent of cell proliferation and is mediated by direct binding of c-MYC to the PKA-Cβ gene promoter sequences. Constitutive expression of PKA-Cβ 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.
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Acknowledgements
We thank Dr B Tycko for the gift of human lambda DASH II genomic library, R Liem for the vimentin probe, U Klein for help with flow cytometric analysis and L Pasqualucci for critical reading of the manuscript. This work was supported in part by NIH grant CA37165 (R Dalla-Favera). M Mattioli was supported by the Universita' degli Studi di Milano, Italy.
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Wu, KJ., Mattioli, M., Morse, H. et al. c-MYC activates protein kinase A (PKA) by direct transcriptional activation of the PKA catalytic subunit beta (PKA-Cβ) gene. Oncogene 21, 7872–7882 (2002). https://doi.org/10.1038/sj.onc.1205986
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DOI: https://doi.org/10.1038/sj.onc.1205986
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