The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1.

The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. Research Abstract Details 

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The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. Abstract Text:

Jing Wang,Lei Yin,Mitchell A Lazar,

Plasminogen activator inhibitor type 1 (PAI-1) is a major physiologic regulator of the fibrinolytic system and has recently gained recognition as a modulator of inflammation and atherosclerosis. PAI-1 exhibits circadian rhythmicity in its expression, peaking in the early morning, which is associated with increased risk for cardiovascular events. However, the mechanisms that determine PAI-1 circadian rhythmicity remain poorly understood. We discovered that the orphan nuclear receptor Rev-erb alpha, a core component of the circadian loop, represses human PAI-1 gene expression through two Rev-erb alpha binding sites in the PAI-1 promoter. Mutations of these sites, as well as RNA interference targeting endogenous Rev-erb alpha and its corepressors, led to increased expression of the PAI-1 gene. Furthermore, glycogen synthase kinase 3beta (GSK3beta) contributes to pai-1 repression by phosphorylating and stabilizing Rev-erb alpha protein, which can be blocked by lithium. Interestingly, serum shock generated circadian oscillations in PAI-1 mRNA in NIH3T3 cells, suggesting that PAI-1 is a direct output gene of the circadian loop. Ectopic expression of a stabilized form of Rev-erb alpha that mimics GSK3beta phosphorylation dramatically dampened PAI-1 circadian oscillations. Thus, our results suggest that Rev-erb alpha is a major determinant of the circadian PAI-1 expression and a potential modulator of the morning susceptibility to myocardial infarction.

The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. Publishing Authors By Initials

J Wang,L Yin,MA Lazar,

For similar genetic processes: gene expression: transcription, genetic research abstracts see: genetic processes: gene expression: transcription, genetic research

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The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 281

Page Numbers: 33842-8

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 11

MONTH: 09

YEAR: 2006

The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. Keywords Mesh Terms:

KEYWORDS: Transcription, Genetic

MESH TERMS: metabolism

Chemical & Substance for Abstract: The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. Information

Substance Name: glycogen synthase kinase 3 beta

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1.

AFFILIATION: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: DK45586

ACRONYM: DK

MEDLINETA: J Biol Chem

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