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Regulation of p53 expression, phosphorylation and subcellular localization by a G-protein-coupled receptor

Oncogene volume 28, pages 3619–3630 (2009)Cite this article

Abstract

G-protein-coupled receptors (GPCRs) have been extremely successful drug targets for a multitude of diseases from heart failure to depression. This superfamily of cell surface receptors have not, however, been widely considered as a viable target in cancer treatment. In this study we show that a classical Gq/11-coupled GPCR, the M3-muscarinic receptor, was able to regulate apoptosis through receptors that are endogenously expressed in the human neuroblastoma cell line, SH-SY5Y, and when ectopically expressed in Chinese hamster ovary (CHO) cells. Stimulation of the M3-muscarinic receptor was shown to inhibit the ability of the DNA-damaging chemotherapeutic agent, etoposide, from mediating apoptosis. This protective response in CHO cells correlated with the ability of the receptor to regulate the expression levels of p53. In contrast, stimulation of endogenous muscarinic receptors in SH-SY5Y cells did not regulate p53 expression but rather was able to inhibit p53 translocation to the mitochondria and p53 phosphorylation at serine 15 and 37. This study suggests the possibility that a GPCR can regulate the apoptotic properties of a chemotherapeutic DNA-damaging agent by regulating the expression, subcellular trafficking and modification of p53 in a manner that is, in part, dependent on the cell type.

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Abbreviations

CHO:

chinese hamster ovary

ERK:

extracellular regulated protein kinase

GPCR:

G-protein-coupled receptor

MAP kinase:

mitogen activated protein kinase

PKA:

protein kinase A

PKC:

protein kinase C

PLC:

phospholipase C

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Acknowledgements

We thank the Wellcome Trust for their support (Grants 073480 and 047600).

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Author notes

  1. L Solyakov and E Sayan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK

    L Solyakov & A B Tobin

  2. Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK

    E Sayan

  3. MRC Toxicology Unit, Leicester, UK

    J Riley & A Pointon

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  1. L Solyakov
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  2. E Sayan
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  3. J Riley
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  4. A Pointon
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  5. A B Tobin
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Corresponding author

Correspondence to A B Tobin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Solyakov, L., Sayan, E., Riley, J. et al. Regulation of p53 expression, phosphorylation and subcellular localization by a G-protein-coupled receptor. Oncogene 28, 3619–3630 (2009). https://doi.org/10.1038/onc.2009.225

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