Abstract
Unique cell cycle control is instituted in confluent osteoblast cultures, driving growth to high density. The postconfluent dividing cells share features with cells that normally exit the cell cycle; p27(kip1) is increased, p21(waf1/cip1) is decreased, free E2F DNA binding activity is reduced, and E2F4 is primarily nuclear. E2F4-p130 becomes the predominant E2F-pocket complex formed on E2F sites, but, unlike the complex that typifies resting cells, cyclin A and CDK2 are also present. Administration of dexamethasone at this, but not earlier stages, results in reduction of cyclin A and CDK2 levels with a parallel decrease in the associated kinase activity, dissociation of cyclin A-CDK2 from the E2F4-p130 complexes, and inhibition of G1/S transition. The glucocorticoid-mediated cell cycle attenuation is also accompanied by, but not attributable to, increased p27(kip1) and decreased p21(waf1/cip1) levels. The attenuation of osteoblast growth to high density by dexamethasone is associated with severe impairment of mineralized extracellular matrix formation, unless treatment commences in cultures that have already grown to high density. Both the antimitotic and the antiphenotypic effects are reversible, and both are antagonized by RU486. Thus, glucocorticoids induce premature attenuation of the osteoblast cell cycle, possibly contributing to the osteoporosis induced by these drugs in vivo.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 19992-20001 |
| Number of pages | 10 |
| Journal | Journal of Biological Chemistry |
| Volume | 275 |
| Issue number | 26 |
| DOIs | |
| State | Published - Jun 30 2000 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
Cite this
Glucocorticoids inhibit developmental stage-specific osteoblast cell cycle : Dissociation of cyclin A-cyclin-dependent kinase 2 from E2F4-p130 complexes. / Smith, Elisheva; Redman, Rebecca A.; Logg, Christopher R.; Coetzee, Gerhard A.; Kasahara, Noriyuki; Frenkel, Baruch.
In: Journal of Biological Chemistry, Vol. 275, No. 26, 30.06.2000, p. 19992-20001.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glucocorticoids inhibit developmental stage-specific osteoblast cell cycle
T2 - Dissociation of cyclin A-cyclin-dependent kinase 2 from E2F4-p130 complexes
AU - Smith, Elisheva
AU - Redman, Rebecca A.
AU - Logg, Christopher R.
AU - Coetzee, Gerhard A.
AU - Kasahara, Noriyuki
AU - Frenkel, Baruch
PY - 2000/6/30
Y1 - 2000/6/30
N2 - Unique cell cycle control is instituted in confluent osteoblast cultures, driving growth to high density. The postconfluent dividing cells share features with cells that normally exit the cell cycle; p27(kip1) is increased, p21(waf1/cip1) is decreased, free E2F DNA binding activity is reduced, and E2F4 is primarily nuclear. E2F4-p130 becomes the predominant E2F-pocket complex formed on E2F sites, but, unlike the complex that typifies resting cells, cyclin A and CDK2 are also present. Administration of dexamethasone at this, but not earlier stages, results in reduction of cyclin A and CDK2 levels with a parallel decrease in the associated kinase activity, dissociation of cyclin A-CDK2 from the E2F4-p130 complexes, and inhibition of G1/S transition. The glucocorticoid-mediated cell cycle attenuation is also accompanied by, but not attributable to, increased p27(kip1) and decreased p21(waf1/cip1) levels. The attenuation of osteoblast growth to high density by dexamethasone is associated with severe impairment of mineralized extracellular matrix formation, unless treatment commences in cultures that have already grown to high density. Both the antimitotic and the antiphenotypic effects are reversible, and both are antagonized by RU486. Thus, glucocorticoids induce premature attenuation of the osteoblast cell cycle, possibly contributing to the osteoporosis induced by these drugs in vivo.
AB - Unique cell cycle control is instituted in confluent osteoblast cultures, driving growth to high density. The postconfluent dividing cells share features with cells that normally exit the cell cycle; p27(kip1) is increased, p21(waf1/cip1) is decreased, free E2F DNA binding activity is reduced, and E2F4 is primarily nuclear. E2F4-p130 becomes the predominant E2F-pocket complex formed on E2F sites, but, unlike the complex that typifies resting cells, cyclin A and CDK2 are also present. Administration of dexamethasone at this, but not earlier stages, results in reduction of cyclin A and CDK2 levels with a parallel decrease in the associated kinase activity, dissociation of cyclin A-CDK2 from the E2F4-p130 complexes, and inhibition of G1/S transition. The glucocorticoid-mediated cell cycle attenuation is also accompanied by, but not attributable to, increased p27(kip1) and decreased p21(waf1/cip1) levels. The attenuation of osteoblast growth to high density by dexamethasone is associated with severe impairment of mineralized extracellular matrix formation, unless treatment commences in cultures that have already grown to high density. Both the antimitotic and the antiphenotypic effects are reversible, and both are antagonized by RU486. Thus, glucocorticoids induce premature attenuation of the osteoblast cell cycle, possibly contributing to the osteoporosis induced by these drugs in vivo.
UR - http://www.scopus.com/inward/record.url?scp=0034733664&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034733664&partnerID=8YFLogxK
U2 - 10.1074/jbc.M001758200
DO - 10.1074/jbc.M001758200
M3 - Article
C2 - 10867026
AN - SCOPUS:0034733664
VL - 275
SP - 19992
EP - 20001
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 26
ER -