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Loss of Serum Response Factor Activity Is the Basis of Reduced C-FOS Expression in Aging Human Fibroblasts

Published online by Cambridge University Press:  29 November 2010

Peter W. Atadja  and
Karl T. Riabowol
Peter W. Atadja
Affiliation:
University of Calgary Health Sciences Centre*
Karl T. Riabowol
Affiliation:
University of Calgary Health Sciences Centre*
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Abstract

Human diploid fibroblasts undergo a limited number of population doublings in vitro and are used widely as a model of cellular aging. Despite growing evidence that cellular aging occurs as a result of altered gene expression, little is known about the activity of transcription factors in aging cells. Here we report that the dramatic reduction in the expression of the transcription factor FOS during cellular aging appears to be due to the inability of another transcription factor, serum response factor (SRF), to bind to its cognate site termed the serum response element (SRE) that is found upstream of several genes including the human c-fos gene. In contrast, the activities of proteins binding to the RNA polymerase “core” element TATA and to the cAMP response element (CRE) were maintained in senescing human fibroblasts. We present evidence that hyperphosphorylation of SRF is responsible for the decreased binding activity seen in late passage cells, as proposed previously for the FOS protein.

Résumé

Les fibroblastes diploïdes humains subissent un nombre limité de dédoublements de population in vitro et sont largement utilisés comme modèle de vieillissement cellulaire. Malgré l'évidence grandissante que le vieillissement cellulaire est dû à une modification de l'expression du gène, l'activité des facteurs de transcription des cellules âgées est encore mal connue. Ici, nous rapportons que la réduction dramatique de l'expression du facteur de transcription fos durant le vieillissement cellulaire semble due à l'incapacité d'un autre facteur de transcription, le facteur réponse de sérum (FRS), de se lier à son site de reconnaissance appelé élément de réponse du sérum (ERS). Ce site est situé en amont de plusieurs gènes comprenant le gène humain c-fos. À l'opposé, les activités des protéines liées à la boîte TATA de la polymérase ARN ainsi qu'à l'élément réponse AMPc sont conservées chez les fibroblastes humains vieillissants. Nous présentons l'évidence que l'hyperphosphorilation du FRS induit une baisse du pouvoir de liaison observée au cours des dernières divisions cellulaires comme ceci a été précédemment suggéré pour la protéine fos.

Keywords

Cellular AgingTranscription FactorsGene Expression.Vieillissement cellulairefacteurs de transcriptionexpression génétique.
Type
Articles
Information
Canadian Journal on Aging / La Revue canadienne du vieillissement , Volume 15 , Issue 1 , Spring/printemps 1996 , pp. 31 - 43
Copyright
Copyright © Canadian Association on Gerontology 1996

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