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Lysophosphatidic acid and adenylyl cyclase inhibitor increase proliferation of senescent human diploid fibroblasts by inhibiting adenosine monophosphate-activated protein kinase

Cited 7 time in Web of Science Cited 9 time in Scopus
Authors
Rhim, Ji-Heon; Jang, Ik-Soon; Song, Kye-Yong; Ha, Moon-Kyung; Cho, Sung-Chun; Yeo, Eui-Ju; Park, Sang Chul
Issue Date
2008-08-30
Publisher
Mary Ann Liebert
Citation
Rejuvenation Res. 2008;11(4):781-792
Keywords
AMP-Activated Protein KinasesAdenine/*analogs & derivatives/pharmacologyAdenylate Cyclase/antagonists & inhibitorsCell Aging/*drug effectsCell Proliferation/*drug effectsCells, CulturedCyclic AMP-Dependent Protein Kinases/metabolism/physiologyCyclin D1/metabolismCyclin-Dependent Kinase Inhibitor p21/metabolism*DiploidyEnzyme Inhibitors/pharmacologyFibroblasts/*drug effects/metabolismHumansLysophospholipids/*pharmacologyModels, BiologicalMultienzyme Complexes/*antagonists & inhibitors/physiologyPhosphorylation/drug effectsProtein-Serine-Threonine Kinases/*antagonists & inhibitors/physiologyS Phase/drug effectsSignal Transduction/drug effects/physiology
Abstract
This study was designed to elucidate the molecular mechanism underlying lysophosphatidic acid (LPA) and adenylyl cyclase inhibitor SQ22536 (ACI)-induced senescent human diploid fibroblast (HDF) proliferation. Because adenosine monophosphate (AMP)-activated protein kinase (AMPK) is known to inhibit cell proliferation, we examined the phosphorylation status of AMPK and p53 and the expression level of p21(waf1/cip1) after treating HDFs with LPA and ACI. Phosphorylation of AMPKalpha on threonine-172 (p-Thr172-AMPKalpha) increases its catalytic activity but phosphorylation on serine-485/491 (p-Ser485/491-AMPKalpha) reduces the accessibility of the Thr172 phosphorylation site thereby inhibiting its catalytic activity. LPA increased p-Ser485/491-AMPKalpha, presumably by activating cAMP-dependent protein kinase (PKA). However, ACI reduced p-Thr172-AMPKalpha by inhibiting the LKB signaling. Our data demonstrated that both LPA and ACI inhibit the catalytic activity of AMPKalpha and p53 by differentially regulating phosphorylation of AMPKalpha, causing increased senescent cell proliferation. These findings suggest that the proliferation potential of senescent HDFs can be modulated through the regulation of the AMPK signaling pathway.
ISSN
1549-1684 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18729810

http://hdl.handle.net/10371/67503
DOI
https://doi.org/10.1089/rej.2008.0709

https://doi.org/10.1089/rej.2008.0709
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biochemistry & Molecular Biology (생화학교실)Journal Papers (저널논문_생화학교실)
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