Regulation of p53 expression, phosphorylation and subcellular localization by a G-protein-coupled receptor.
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 G(q/11)-coupled GPCR, the M(3)-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 M(3)-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.
Solyakov
L
L
Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK.
Sayan
E
E
Riley
J
J
Pointon
A
A
Tobin
A B
AB
D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D043587:Receptor, Muscarinic M3; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D020169:Caspases