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

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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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Author notes

  1. Kou-Juey Wu

    Present address: Department of Medical Genetics, National Taiwan University Hospital, Taipei, 100, Taiwan

  2. Kou-Juey Wu and Michela Mattioli: These two authors contributed equally to this work

Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, 10032, NY, USA

    Kou-Juey Wu, Michela Mattioli & Riccardo Dalla-Favera

  2. Department of Pathology, Columbia University, New York, 10032, NY, USA

    Riccardo Dalla-Favera

  3. Department of Genetics & Development, Columbia University, New York, 10032, NY, USA

    Riccardo Dalla-Favera

  4. Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA

    Herbert C Morse III

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  1. Kou-Juey Wu
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  2. Michela Mattioli
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  3. Herbert C Morse III
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  4. Riccardo Dalla-Favera
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Correspondence to Riccardo Dalla-Favera.

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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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