Overexpression of serum amyloid A-activating factor 1 inhibits cell proliferation by the induction of cyclin-dependent protein kinase inhibitor p21WAF-1/Cip-1/Sdi-1 expression

J Immunol. 2004 Apr 15;172(8):5006-15. doi: 10.4049/jimmunol.172.8.5006.

Abstract

Inflammation-responsive transcription factor, serum amyloid A-activating factor 1 (SAF-1), has been shown to regulate several genes, including serum amyloid A, gamma-fibrinogen, and matrix metalloproteinase 1, whose abnormal expression is associated with the pathogenesis of arthritis, atherosclerosis, and amyloidosis. Prolonged high level expression of SAF-1 in cultured cells failed to produce any stable cell line that overexpresses SAF-1. To test the fate of SAF-1-overexpressing cells, the cells were monitored for growth and morphological changes over time. The cells that were programmed to overproduce SAF-1 were found to undergo growth arrest and reduce DNA synthesis within 3 days after transfection. These cells undergo marked morphological changes from typical fibroblasts to round morphology and gradually cease to exist. Microarray analysis for cell cycle-specific genes in SAF1-transfected cells identified several candidate genes whose expression levels were altered during SAF-1 overexpression. Cdk inhibitor protein p21 was significantly affected by SAF-1; its expression level was highly induced by cellular conditions where SAF-1 is abundant. The increased level of p21 in the cell drives it to a growth arrest mode, a condition previously found to be controlled by p53. In this study we provide evidence that, similar to p53, SAF-1 is able to activate p21 gene expression by promoting transcription directly via its interaction with the p21 promoter. Together these data indicate that SAF-1 controls cell cycle progression via p21 induction, and pathophysiological conditions that favor overexpression of SAF-1, such as an acute inflammatory condition, can trigger cellular growth arrest.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division / genetics
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclins / biosynthesis*
  • Cyclins / genetics
  • Cyclins / metabolism
  • Cyclins / physiology
  • DNA Footprinting
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Deoxyribonuclease I
  • Female
  • Gene Expression Regulation
  • Growth Inhibitors / biosynthesis*
  • Growth Inhibitors / genetics*
  • Growth Inhibitors / physiology
  • Humans
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Rabbits
  • Synovial Membrane / cytology
  • Synovial Membrane / metabolism
  • Transcription Factors
  • Transcriptional Activation
  • Transfection

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Growth Inhibitors
  • RNA, Messenger
  • Transcription Factors
  • c-MYC-associated zinc finger protein
  • Cyclin-Dependent Kinases
  • Deoxyribonuclease I