Alterations in the molecular response to DNA damage during cellular aging of cultured fibroblasts: Reduced AP‐1 activation and collagenase gene expression

Augustine M.K. Choi, Robert J. Pignolo, Colette M.J.Ap Rhys, Vincent J. Cristofalo, Nikki J. Holbrook

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Transcriptional activation of c‐fos in response to both serum stimulation and DNA damage requires the serum response element. The inability of in vitro aged or senescent fibroblasts to proliferate in response to serum has been shown to be associated with repressed c‐fos expression and reduced AP‐1 binding activity. In contrast, we have observed similar levels of c‐fos mRNA and protein expression in young (early passage) and old (late passage) cells following their treatment with ultraviolet (UV) irradiation or methyl methanesulfonate (MMS). Thus, the early events in the signal transduction pathway leading to transcriptional activation of c‐fos following DNA damage are distinct from those mediating the gene's expression in response to mitogenic stimulation. Despite normal levels of c‐fos expression, we observed a reduced level of AP‐1 binding activity in old cells relative to young cells treated with UV irradiation or MMS. Reduced AP‐1 binding activity is associated with reduced expression of the AP‐1‐dependent gene, collagenase, in old cells treated with DNA damaging agents. Since other DNA damage‐inducible genes also contain an AP‐1 regulatory element presumed to play a role in their expression, reduced AP‐1 binding activity is likely to have a major impact on the old cell's ability to respond appropriately to DNA damage. © 1995 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)65-73
Number of pages9
JournalJournal of Cellular Physiology
Volume164
Issue number1
DOIs
StatePublished - Jul 1995

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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