S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biochemistry & Molecular Biology (생화학교실) Journal Papers (저널논문_생화학교실)
Lysophosphatidic acid and adenylyl cyclase inhibitor increase proliferation of senescent human diploid fibroblasts by inhibiting adenosine monophosphate-activated protein kinase
- Rhim, Ji-Heon; Jang, Ik-Soon; Song, Kye-Yong; Ha, Moon-Kyung; Cho, Sung-Chun; Yeo, Eui-Ju; Park, Sang Chul
- Issue Date
- Mary Ann Liebert
- Rejuvenation Res. 2008;11(4):781-792
- AMP-Activated Protein Kinases; Adenine/*analogs & derivatives/pharmacology; Adenylate Cyclase/antagonists & inhibitors; Cell Aging/*drug effects; Cell Proliferation/*drug effects; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases/metabolism/physiology; Cyclin D1/metabolism; Cyclin-Dependent Kinase Inhibitor p21/metabolism; *Diploidy; Enzyme Inhibitors/pharmacology; Fibroblasts/*drug effects/metabolism; Humans; Lysophospholipids/*pharmacology; Models, Biological; Multienzyme Complexes/*antagonists & inhibitors/physiology; Phosphorylation/drug effects; Protein-Serine-Threonine Kinases/*antagonists & inhibitors/physiology; S Phase/drug effects; Signal Transduction/drug effects/physiology
- 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.
- 1549-1684 (Print)
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