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Tom Matthews tmatth at netcom.ca
Mon Aug 31 18:31:38 EST 1998


T.D. Laing wrote:

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

I just want to note that your use of the term "senescent" here is not
"technically" correct. The technical meaing of "senescent cells" is
cells which are no longer able to divide. The abstract which you posted
is most interesting, but it contrasts younger cells with older cells
which are not necessarily senescent.
 
> 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
 control
 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
 (TGF
 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
 factor
 (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
 TGF 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.

--Tom 
Tom Matthews
 
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