N-acetyl-seryl-aspartyl-lysyl-proline inhibits DNA synthesis in human mesangial cells via up-regulation of cell cycle modulators.
N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) was originally reported as a natural inhibitor of the proliferation of stem cells. To elucidate whether Ac-SDKP inhibits the proliferation of human mesangial cells, we examined the effect of Ac-SDKP on fetal calf serum (FCS)- or platelet-derived growth factor (PDGF)-BB-induced DNA synthesis and a cell proliferation. Ac-SDKP inhibited PDGF-BB- or FCS-induced DNA synthesis without cellular toxicity. The protein expression of p53 and p27kip1 was significantly increased by Ac-SDKP. Ac-SDKP also up-regulated the PDGF-BB-stimulated expression of p21cip1 and suppressed PDGF-BB-induced cyclin D1 expression. In p53 knock-out human mesangial cells made with small interference RNA, the protein expression of p21cip1 and p27kip1 was also decreased and the inhibitory effect of Ac-SDKP on mesangial proliferation was completely abolished. Ac-SDKP increased the stability of p53 protein as demonstrated by pulse-chase experiment. These results suggest that p53 is the key mediator of Ac-SDKP-induced inhibition of DNA synthesis through the up-regulation of cell cycle modulators, highlighting a potential effect of Ac-SDKP on various progressive renal diseases.
Kanasaki
Keizo
K
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Haneda
Masakazu
M
Sugimoto
Toshiro
T
Shibuya
Kazuyuki
K
Isono
Motohide
M
Isshiki
Keiji
K
Araki
Shin-ichi
S
Uzu
Takashi
T
Kashiwagi
Atsunori
A
Koya
Daisuke
D
D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D019384:Nucleic Acid Synthesis Inhibitors; D009842:Oligopeptides; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; C058504:goralatide