Abstract:
:Vascular smooth muscle cell (VSMC) proliferation occurs in vascular obstructive events such as atherosclerosis and restenosis. We previously showed that Notch receptors are induced in smooth muscle cells during vascular remodeling. Our goal was to determine the mechanisms employed by Notch signaling to regulate proliferation. Activation of Notch1 and Notch4 induced the VSMC-selective target genes HRT1 and HRT2, promoted cell cycle transit in smooth muscle cells, and led to loss of density-dependent growth inhibition. This was associated with a reduction in levels of the cyclin-dependent kinase inhibitor (cdk) p27(kip1). Over-expression of p27(kip1) resulted in a dose-dependent rescue of the Notch-induced phenotype and exit from the cell cycle. In addition, HRT2 expression was sufficient to promote S-phase entry, and we demonstrate that HRT2 interacts directly with the p27(kip1) promoter to repress transcription. Transcriptional repression occurred within the approximately 774 bp minimal p27(kip1) promoter region and mutational analysis demonstrated that repression is largely dependent on a conserved class-C domain. Our data show that Notch signaling acts to promote a proliferative phenotype in VSMC by modulation of the G1/S-phase checkpoint. In addition, we define a novel mechanism by which the Notch effector, HRT2, interacts directly with the class-C domain of the p27(kip1) promoter, repressing its expression. These studies identify a novel transcriptional target of HRT2, and show that Notch effectors directly control cell cycle regulatory components. We suggest that this mechanism is relevant to hyperproliferative states in VSMC seen during vascular remodeling and repair.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Havrda MC,Johnson MJ,O'Neill CF,Liaw Ldoi
10.1160/TH06-04-0224subject
Has Abstractpub_date
2006-09-01 00:00:00pages
361-70issue
3eissn
0340-6245issn
2567-689Xpii
06090361journal_volume
96pub_type
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1055/s-0038-1676818
更新日期:2019-02-01 00:00:00
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journal_title:Thrombosis and haemostasis
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pub_type: 杂志文章
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,评审
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH11-04-0229
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH06-04-0185
更新日期:2006-07-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
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更新日期:1998-09-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,多中心研究,随机对照试验
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH15-08-0653
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journal_title:Thrombosis and haemostasis
pub_type: 临床试验,杂志文章
doi:
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1996-04-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH11-04-0220
更新日期:2011-10-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH17-04-0248
更新日期:2017-11-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 临床试验,杂志文章
doi:
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1055/s-0040-1712448
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
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更新日期:1979-10-31 00:00:00
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更新日期:2013-04-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,随机对照试验
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更新日期:2017-04-03 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,多中心研究
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更新日期:2008-05-01 00:00:00
abstract::A patient with an 18 year history of recurrent arterial thrombosis and no evidence of atherosclerosis or embolism of cardiac origin presented with a prolonged thrombin clotting time when performed with human thrombin. The bovine thrombin clotting time was only slightly prolonged. During 30 months of follow-up, the thr...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
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更新日期:1992-02-03 00:00:00
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pub_type: 杂志文章
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更新日期:2004-07-01 00:00:00
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pub_type: 杂志文章
doi:10.1160/TH10-12-0782
更新日期:2011-06-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,随机对照试验
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更新日期:2014-12-01 00:00:00