Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.697092
Title: Cell growth regulation by muscarinic acetylcholine receptors
Author: Burdon, Drew
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2002
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Abstract:
The growth response of Chinese hamster ovary (CHO) cells to activation of recombinantly expressed G protein-coupled muscarinic M2 or M3 acetylcholine (ACh) receptors has been assessed. Activation of these receptors leads to divergent growth responses: M2 ACh receptor activation causes an increase in DNA synthesis, whereas M3 ACh receptor activation causes a dramatic inhibition of DNA synthesis. The M3 ACh receptor-mediated growth inhibition has been characterised, and shown to comprise a G1-phase cell cycle arrest, involving an increase in p21Cip1/Waf1 protein expression. Further, a receptor-mediated increase in p21Cip1/Waf1 association with cyclin-dependent kinase 2 (CDK2) leads to a decrease in CDK2 activity and an accumulation of hypophosphorylated retinoblastoma protein (pRb). The increase p21Cip1/Waf1 expression is due at least in part to an increase p21Cip1/Waf1 mRNA although no receptor-mediated change in candidate transcription factor activities could be detected. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activation profiles suggested two alternative hypotheses to account for the receptor-mediated growth arrest. However, pharmacological and biochemical data demonstrate that ERK, JNK and p38 MAPK are not involved in the growth regulation, whilst inhibition of PKC partially ablates the growth arrest. Data demonstrate that both M3 ACh receptor-mediated ERK and JNK activities may be dependent on liberated G-protein bg subunits, whilst the growth arrest is not perturbed by bg subunit sequestration. Data presented reveal a MAPK-independent mechanism of growth regulation that may involve coping of the M3 ACh receptor to heterotrimeric G-protein families other than Gq/11.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.697092  DOI: Not available
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