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T.D. Laing tdlaing at
Mon Aug 31 16:39:26 EST 1998

In article <35EA053F.4D69 at>, tmatth at wrote:

[snip some very fascinating statements and comments]

> > In order to determine whether these factors have any
> > effect on senescent cell appearance I propose to conduct several experiments
> > which will determine:


> >      3. Test protein turnover and overall profile in senescent cells as
> > compared to dividing cells.

Senescent cells appear to express more matrix metalloproteinases than
younger cells, and respond differently to TGF-beta (from Medline):

Exp Gerontol 1996 Jan;31(1-2):207-223 

Differential effects of transforming growth factor-beta 1 on the
expression of matrix metalloproteinases and tissue inhibitors of
metalloproteinases in young and old human fibroblasts.

Edwards DR, Leco KJ, Beaudry PP, Atadja PW, Veillette C, Riabowol KT

Department of Pharmacology and Therapeutics, University of Calgary,
Alberta, Canada. 

The balance between the activities of matrix metalloproteinases (MMPs) and
the tissue inhibitors of metalloproteinases (TIMPs) is an important
point in tissue remodeling. Previous studies have demonstrated elevated
expression of the MMPs collagenase and stromelysin-1 by aged human diploid
fibroblasts compared to early-passage cultures. We show here that aging
cells display an altered response to transforming growth factor-beta 1
beta 1) that selectively affects MMP mRNA expression. In both young and
old cells, phorbol myristoyl-13 acetate (PMA) induced the expression of
transcripts of collagenase, stromelysin-1, gelatinase-B, TIMP-1, and
TIMP-3. In young cells, TGF beta 1 reciprocally modulated PMA-induced MMP
and TIMP gene expression leading to reduced levels of transcripts for the
MMPs and augmented accumulation of TIMP-1 and TIMP-3 mRNAs.
However, repressing effects of TGF beta 1 on collagenase, stromelysin-1,
and gelatinase-B RNA expression were not apparent in old cells, though
induction of the TIMP genes was unimpaired. By electrophoretic mobility
shift analysis the nuclear transcription factors AP1 and serum response
(SRF) showed reduced levels of DNA binding activities in old fibroblasts
compared to young cells. A probe for the TGF beta-inhibitory element (TIE)
gave equivalent levels of complexes with nuclear extracts from both types
of cells, though of different mobilities. We conclude that the effects of
beta 1 on MMP and TIMP gene expression involve different cellular
intermediaries, and suggest that altered composition or modification of
TIE binding factors in aging cells may underlie the failure of TGF beta
1-mediated transcription repression. This mechanism may contribute to
elevated constitutive
expression of MMPs in old cells and to the connective tissue deterioration
that accompanies the aging process. 


T.D. Laing
tdlaing at

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