C/EBPalpha expression is partially regulated by C/EBPbeta in response to DNA damage and C/EBPalpha-deficient

R Ranjan1, E A Thompson, K Yoon

  • 1Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA.

Oncogene
|July 8, 2009
PubMed

Insights

CCAAT/enhancer-binding protein (C/EBP)alpha is crucial for the G1 DNA damage checkpoint in fibroblasts. C/EBPbeta regulates C/EBPalpha induction following DNA damage, highlighting a novel regulatory pathway.

Area of Science:

  • Cellular biology
  • Molecular genetics
  • DNA damage response

Background:

  • CCAAT/enhancer-binding protein (C/EBP)alpha is a transcription factor involved in cell differentiation and inflammation.
  • The G1 checkpoint prevents cells with damaged DNA from entering the S-phase.
  • The role of C/EBPalpha in the DNA damage response has not been fully elucidated.

Purpose of the Study:

  • To investigate the role of C/EBPalpha in the G1 DNA damage checkpoint.
  • To identify upstream regulators of C/EBPalpha induction by DNA-damaging agents.
  • To determine the functional significance of C/EBPbeta in C/EBPalpha regulation.

Main Methods:

  • Primary fibroblast cultures were treated with DNA-damaging agents (UVB, MNNG).
  • Cell cycle progression was analyzed in wild-type and C/EBPalpha-deficient fibroblasts.
  • Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) were used to assess C/EBPbeta binding.
  • C/EBPalpha induction was examined in C/EBPbeta-deficient fibroblasts.

Main Results:

  • C/EBPalpha is highly inducible by various DNA-damaging agents in primary fibroblasts.
  • Fibroblasts deficient in C/EBPalpha exhibit an impaired G1 checkpoint and inappropriate S-phase entry.
  • C/EBPbeta binds to the C/EBPalpha promoter and is required for C/EBPalpha induction following DNA damage.
  • C/EBPalpha induction by DNA damage does not depend on p53.

Conclusions:

  • C/EBPalpha plays a critical role in the DNA damage-induced G1 checkpoint.
  • C/EBPbeta acts as a novel regulator of C/EBPalpha in response to DNA damage.
  • These findings reveal a new regulatory mechanism controlling cell cycle progression following DNA damage.

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