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Physical and functional association between GADD153 and CCAAT/enhancer-binding protein beta during cellular stress.

GADD153, a ubiquitously expressed member of the CCAAT/enhancer-binding protein (C/EBP) family is induced by a wide variety of growth-arresting and DNA-damaging agents. Functionally, GADD153 has been postulated to act as a dominant-negative regulator of C/EBPs. Therefore we sought to gain evidence for interactions between GADD153 and other C/EBPs during cellular responses to stress. In this report we have demonstrated that treatment of rat pheochromocytoma PC12 cells with sodium arsenite leads to enhanced expression of C/EBP-beta and GADD153 (growth arrest and DNA damage inducible gene 153) but not other C/EBPs. Coimmunoprecipitation experiments provided evidence for the formation of endogenous GADD153-C/EBP-beta complexes in arsenite-treated cells. Additional experiments were performed to determine the role of such complexes in regulating GADD153 expression. Previous studies in our laboratory demonstrated that the GADD153 promoter contains a C/EBP binding site through which other C/EBPs interact to transactivate GADD153 expression in liver hepatoma cells. Here, we demonstrate that extracts prepared from arsenite-treated PC12 cells likewise show increased amounts of factors capable of binding to the GADD153-C/EBP site and that these complexes are comprised at least in part of C/EBP-beta. Forced expression of C/EBP-beta was found to be capable of transactivating the GADD153 promoter in PC12 cells cotransfected with plasmids expressing a GADD153 reporter gene and C/EBP-beta protein. However, overexpression of GADD153 inhibited the transactivation of the GADD153 promoter by C/EBP-beta. These findings provide evidence for an autoregulatory loop in which stress-induced GADD153 feeds back to attenuate GADD153 expression during the cellular response to stress.

Pubmed ID: 8662954

Authors

  • Fawcett TW
  • Eastman HB
  • Martindale JL
  • Holbrook NJ

Journal

The Journal of biological chemistry

Publication Data

June 14, 1996

Associated Grants

None

Mesh Terms

  • Adrenal Gland Neoplasms
  • Animals
  • Arsenites
  • Base Sequence
  • Binding Sites
  • CCAAT-Enhancer-Binding Proteins
  • Consensus Sequence
  • Cricetinae
  • DNA Damage
  • DNA-Binding Proteins
  • Molecular Sequence Data
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • PC12 Cells
  • Pheochromocytoma
  • Promoter Regions, Genetic
  • Rats
  • Sp1 Transcription Factor
  • Stress, Physiological
  • Transcription Factor CHOP
  • Transcription Factors
  • Transcription, Genetic