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The regulation of phosphoenolpyruvat...

Chakravarty, Kaushik.

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The regulation of phosphoenolpyruvate carboxykinase-C gene transcription by sterol regulatory element binding protein-1.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The regulation of phosphoenolpyruvate carboxykinase-C gene transcription by sterol regulatory element binding protein-1./
作者:	Chakravarty, Kaushik.
面頁冊數:	129 p.
附註:	Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4766.
Contained By:	Dissertation Abstracts International64-10B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3107690
ISBN:	0496552384

The regulation of phosphoenolpyruvate carboxykinase-C gene transcription by sterol regulatory element binding protein-1.
Chakravarty, Kaushik.

The regulation of phosphoenolpyruvate carboxykinase-C gene transcription by sterol regulatory element binding protein-1. - 129 p.

Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4766.

Thesis (Ph.D.)--Case Western Reserve University (Health Sciences), 2003.

My research has established that the Sterol Regulatory Element-binding Protein-1 (SREBP-1) is the transcriptional mediator for insulin control of expression of the gene for the cytosolic form of Phosphoenolpyruvate Carboxykinase (GTP) (EC 4. 1. 1. 32) (PEPCK-C). SREBP-1c, when introduced into primary hepatocytes, dramatically decreased the level of mRNA for PEPCK-C, the rate-limiting enzyme in gluconeogenesis. It also completely blocked the induction of PEPCK-C gene transcription by protein kinase A. A 10-fold induction of PKA-stimulated PEPCK-C gene transcription caused by the co-activator CBP was inhibited by SREBP-1c. Increasing concentrations of dnSREBP-1c reversed the negative effect of insulin on PEPCK-C gene transcription. It also reversed the strong negative effect of E1A and nuclear factor I on PKA-stimulated transcription from the PEPCK-C gene promoter. In addition to SREBP-1c, both SREBP-1a and SREBP-2 inhibited transcription of the gene for PEPCK-C. Two SREBP Regulatory Elements (SREs) in the PEPCK-C gene promoter (-322 to -313 and -590 to -581) were identified by their ability to bind SREBP-la and SREBP-1c with low affinity. The addition of Upstream Stimulatory Activity (USA; nuclear protein purified from HeLa nuclei) resulted in synergistic binding of SREBP-1a and SREBP-1c to these sites. Mutating the SREs at -322 and -590 increased both basal (5-fold) and PKA-stimulated transcription (8 to 27-fold) from the PEPCK-C gene promoter. There was a total loss of SREBP-1c inhibition of gene transcription when both sites were mutated. The SRE at -590 differs by a single base pair (T/A) from the consensus SRE in the gene for the LDL receptor. Rather than causing an inhibition, introduction of the consensus SRE into the PEPCK-C gene promoter decreased SREBP-1c binding and caused a 10-fold stimulation in basal gene transcription from the promoter. The SRE in the PEPCK-C gene promoter has an SP1 site on the opposite strand of the DNA. SP1 binds to the promoter independently of SREBP-1c but competes with SREBP-1c for binding when both are present. The T/A modification decreased the binding of SP1 to the promoter in the presence of SREBP-1. This may account for the marked stimulation by SREBP-1c of transcription from the PEPCK-C gene promoter that had been modified to contain the SREBP-1 regulatory element from the LDLr gene. Recently a model has been proposed by Bennett and Osborne (Bennett and Osborne, 2000) to explain the regulation of the LDL receptor gene promoter by SREBP-1. This model proposes that SREBP-1 binds to the SRE, which recruits SP1 to bind to an adjacent site. Next, the bound SP1 destabilizes the DNA-bound SREBP-1, which then falls off the promoter and is rapidly degraded. This model demonstrates the reversible and transient regulation by SREBP-1 on the LDLr gene promoter. The results of research suggest that PEPCK-C gene transcription is regulated by SREBP-1 in a similar fashion and have established that SREBP-1c mediates the insulin inhibition of PEPCK-C gene transcription in the liver.

ISBN: 0496552384Subjects--Topical Terms:

1017719
Biology, Molecular.

The regulation of phosphoenolpyruvate carboxykinase-C gene transcription by sterol regulatory element binding protein-1.
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