Abstract
A large body of evidence has demonstrated that normal human fibroblasts have a limited division potential in culture and underwent senescence, a process whereby cells became arrested in the G 1 phase of the cell cycle and overexpressed a DNA synthesis inhibitor(s). Cyclin-dependent kinase two (Cdk2) is required for the promotion of the G 1-to-S phase transition in human cells. Senescent fibroblasts contain intact cyclin-Cdk2 complexes but cannot induce Cdk2 protein kinase activity in response to mitogen stimulation. Recently, we cloned p21(Sdi1), a potent inhibitor of DNA synthesis and Cdk2 kinase activity, from a senescent cell cDNA library and demonstrated that it was expressed at significantly higher levels in senescent cells than actively proliferating cells. In contrast to actively dividing cells, mitogen-stimulated senescent cells do not down-regulate the expression of p21(Sdi1) and do not express late G 1 phase gene products that are required for entry into S phase. We suggest that the inability of mitogen-stimulated senescent cells to down-regulate p21(Sdi1) levels contributes to the resulting lack of late G 1 gene expression and failure to traverse the G 1/S phase boundary.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 315-329 |
| Number of pages | 15 |
| Journal | Canadian Journal on Aging |
| Volume | 15 |
| Issue number | 2 |
| State | Published - Jun 1996 |
| Externally published | Yes |
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Keywords
- Cdk inhibitor
- Cdk2
- cell cycle
- DNA synthesis
- p21(Sdi1)
ASJC Scopus subject areas
- Aging
Cite this
Regulation of the p21(Sdi1/Cip1/Waf1) DNA synthesis inhibitor in senescent human diploid fibroblasts. / Robetorye, Ryan S.; Smith, James R.
In: Canadian Journal on Aging, Vol. 15, No. 2, 06.1996, p. 315-329.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of the p21(Sdi1/Cip1/Waf1) DNA synthesis inhibitor in senescent human diploid fibroblasts
AU - Robetorye, Ryan S.
AU - Smith, James R.
PY - 1996/6
Y1 - 1996/6
N2 - A large body of evidence has demonstrated that normal human fibroblasts have a limited division potential in culture and underwent senescence, a process whereby cells became arrested in the G 1 phase of the cell cycle and overexpressed a DNA synthesis inhibitor(s). Cyclin-dependent kinase two (Cdk2) is required for the promotion of the G 1-to-S phase transition in human cells. Senescent fibroblasts contain intact cyclin-Cdk2 complexes but cannot induce Cdk2 protein kinase activity in response to mitogen stimulation. Recently, we cloned p21(Sdi1), a potent inhibitor of DNA synthesis and Cdk2 kinase activity, from a senescent cell cDNA library and demonstrated that it was expressed at significantly higher levels in senescent cells than actively proliferating cells. In contrast to actively dividing cells, mitogen-stimulated senescent cells do not down-regulate the expression of p21(Sdi1) and do not express late G 1 phase gene products that are required for entry into S phase. We suggest that the inability of mitogen-stimulated senescent cells to down-regulate p21(Sdi1) levels contributes to the resulting lack of late G 1 gene expression and failure to traverse the G 1/S phase boundary.
AB - A large body of evidence has demonstrated that normal human fibroblasts have a limited division potential in culture and underwent senescence, a process whereby cells became arrested in the G 1 phase of the cell cycle and overexpressed a DNA synthesis inhibitor(s). Cyclin-dependent kinase two (Cdk2) is required for the promotion of the G 1-to-S phase transition in human cells. Senescent fibroblasts contain intact cyclin-Cdk2 complexes but cannot induce Cdk2 protein kinase activity in response to mitogen stimulation. Recently, we cloned p21(Sdi1), a potent inhibitor of DNA synthesis and Cdk2 kinase activity, from a senescent cell cDNA library and demonstrated that it was expressed at significantly higher levels in senescent cells than actively proliferating cells. In contrast to actively dividing cells, mitogen-stimulated senescent cells do not down-regulate the expression of p21(Sdi1) and do not express late G 1 phase gene products that are required for entry into S phase. We suggest that the inability of mitogen-stimulated senescent cells to down-regulate p21(Sdi1) levels contributes to the resulting lack of late G 1 gene expression and failure to traverse the G 1/S phase boundary.
KW - Cdk inhibitor
KW - Cdk2
KW - cell cycle
KW - DNA synthesis
KW - p21(Sdi1)
UR - http://www.scopus.com/inward/record.url?scp=0029740819&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029740819&partnerID=8YFLogxK
M3 - Article
VL - 15
SP - 315
EP - 329
JO - Canadian Journal on Aging/La Revue canadienne du vieillissment/Canadian Public Policy/Analyse de Politiques
JF - Canadian Journal on Aging/La Revue canadienne du vieillissment/Canadian Public Policy/Analyse de Politiques
SN - 0714-9808
IS - 2
ER -