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Growth inhibition by the muscarinic M3 acetylcholine receptor: evidence for p21Cip1/Waf1 involvement in G1 arrest

By Drew Burdon, Rajnikant Patel, R.A. John Challiss and Jonathan L. Blank

Abstract

This paper was published as Biochemical Journal, 2002, 367 (Part 2), pp.549-559. The final version of record is available at http://www.biochemj.org/bj/367/bj3670549.htm. Doi: 10.1042/bj20020446Metadata only entryWe have assessed the growth response of Chinese-hamster ovary (CHO) cells to activation of recombinantly expressed G-protein-coupled muscarinic M2 or M3 acetylcholine receptors (AChRs). We show that activation of these receptors leads to divergent growth responses: M2 AChR activation causes an increase in DNA synthesis, whereas M3 AChR activation causes a dramatic decrease in DNA synthesis. We have characterized the M3 AChR-mediated growth inhibition and show that it involves a G1 phase cell-cycle arrest. Further analysis of this arrest indicates that it involves an increase in expression of the cyclin-dependent kinase (CDK) inhibitor, p21Cip1/Waf1 (where Cip1 is CDK-interacting protein 1 and Waf1 is wild-type p53-associated fragment 1), in response to M3 AChR activation. This increase in protein expression leads to an increase in p21Cip1/Waf1 association with CDK2, a decrease in CDK2 activity and an accumulation of hypophosphorylated retinoblastoma protein. The increased p21Cip1/Waf1 expression is due, at least in part, to an increase in p21Cip1/Waf1 mRNA, and receptor-mediated changes in phosphorylation of c-Jun provide a mechanism to account for this p21Cip1/Waf1 transcriptional regulation. Evaluation of the extracellular signal-regulated protein kinase and c-Jun N-terminal kinase activities has shown striking differences in the profiles of activation of these mitogen-activated protein kinases by the M2 and M3 AChRs, and their potential involvement in mediating growth arrest by the M3 AChR is discussed

Publisher: Portland Press
Year: 2002
DOI identifier: 10.1042/bj20020446
OAI identifier: oai:lra.le.ac.uk:2381/1541
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