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Protein kinase A isozyme switching: eliciting differential cAMP signaling and tumor reversion

Oncogene volume 23, pages 8847–8856 (2004)Cite this article

Abstract

The cAMP-dependent protein kinase types I (PKA-I) and II (PKA-II), composed of identical catalytic (C) subunits but distinct regulatory (R) subunits (RI versus RII), are expressed in a balance of cell growth and differentiation. Distortion of this balance may underlie tumorigenesis and tumor growth. Here, we used PC3M prostate carcinoma cells as a model to overexpress wild type and mutant R and C subunit genes and examined the effects of differential expression of these genes on tumor growth. Only the RIIβ and mutant RIα-P (a functional mimic of RIIβ) transfectants exhibited growth inhibition in vitro, reverted phenotype, and apoptosis, and inhibited in vivo tumor growth. DNA microarrays demonstrated that RIIβ and RIα-P overexpression upregulated a cluster of differentiation genes, while downregulating transformation and proliferation signatures. Overexpression of RIα and Cα, which upregulated PKA-I, elicited the expression signatures opposite that elicited by RIIβ overexpression. Total colocalization of Cα and RIIβ seen by confocal microscopy in the RIIβ cell nucleus supports the opposed genomic regulation demonstrated between Cα and RIIβ cells. Differential expression of PKA R subunits may therefore serve as a tumor-target-based gene therapy for PC3M prostate and other cancers.

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Acknowledgements

We thank Cheryl Pellerin of Palladian Partners, Inc., who provided editorial support for the National Cancer Institute under Contract N02-BC-76512/C2700212.

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Authors and Affiliations

  1. Cellular Biochemistry Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, 20892-1750, MD, USA

    Catherine L Neary, Maria Nesterova, Yee Sook Cho & Yoon S Cho-Chung

  2. DNA Array Unit, National Institute on Aging, National Institutes of Health, Baltimore, 21224, MD, USA

    Chris Cheadle & Kevin G Becker

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  1. Catherine L Neary
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  2. Maria Nesterova
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  3. Yee Sook Cho
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  4. Chris Cheadle
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Correspondence to Yoon S Cho-Chung.

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Neary, C., Nesterova, M., Cho, Y. et al. Protein kinase A isozyme switching: eliciting differential cAMP signaling and tumor reversion. Oncogene 23, 8847–8856 (2004). https://doi.org/10.1038/sj.onc.1208165

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