Assignment of the membrane attachment, DNA binding, and transcriptional activation domains of sterol regulatory element-binding protein-1 (SREBP-1).

The mammalian gene for SREBP-1 (sterol-regulatory-element-binding protein 1) contains two promoters that control the production of two proteins, SREBP-1a and -1c, and each contains a unique N-terminal transcriptional activation domain, but they are otherwise identical. The relative level of each mRNA varies from tissue to tissue and they respond differently to regulatory stimuli. SREBP-1c is more abundantly expressed in liver, where its level is also regulated by insulin and liver X receptor activators, and it is also autoregulated by SREBPs. In contrast, SREBP-1a mRNA levels are relatively low and constant in different tissues and few studies have specifically analysed its pattern of expression and regulation. In the present study, we show that the promoter for SREBP-1a is contained in a very small promoter-proximal region containing two Sp1 sites. The small and relatively simple structure for its promoter provides an explanation for the low level of SREBP-1a expression. Additionally, since Sp1 has been implicated in the modest regulation of several genes by insulin, its involvement in the expression of the SREBP-1a promoter provides an explanation for the modest insulin regulation observed in animal experiments.

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Functional antagonism between inhibitor of DNA binding (Id) and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1c (ADD1/SREBP-1c) trans-factors for the regulation of fatty acid synthase promoter in adipocytes

Biochemical Journal ◽

10.1042/0264-6021:3440873 ◽

1999 ◽

Vol 344 (3) ◽

pp. 873 ◽

Cited By ~ 18

Author(s):

Marthe MOLDES ◽

Muriel BOIZARD ◽

Xavier LE LIEPVRE ◽

Bruno FÈVE ◽

Isabelle DUGAIL ◽

...

Keyword(s):

Fatty Acid ◽

Dna Binding ◽

Fatty Acid Synthase ◽

Binding Protein ◽

Regulatory Element ◽

Differentiation Factor ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Functional Antagonism ◽

Inhibitor Of Dna Binding

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Activation Domains from Both Monomers Contribute to Transcriptional Stimulation by Sterol Regulatory Element-binding Protein Dimers

Journal of Biological Chemistry ◽

10.1074/jbc.m411222200 ◽

2004 ◽

Vol 280 (5) ◽

pp. 3338-3345 ◽

Cited By ~ 24

Author(s):

Shrimati Datta ◽

Timothy F. Osborne

Keyword(s):

Binding Protein ◽

Regulatory Element ◽

Activation Domains ◽

Protein Dimers ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Transcriptional Stimulation

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The flavone apigenin blocks nuclear translocation of sterol regulatory element-binding protein-2 in the hepatic cells WRL-68

British Journal Of Nutrition ◽

10.1017/s0007114515001312 ◽

2015 ◽

Vol 113 (12) ◽

pp. 1844-1852 ◽

Cited By ~ 5

Author(s):

Tsz Yan Wong ◽

Shu-Mei Lin ◽

Lai K. Leung

Keyword(s):

Dna Binding ◽

Nuclear Translocation ◽

Binding Protein ◽

Regulatory Element ◽

Plasma Lipid ◽

Binding Activity ◽

Dna Binding Activity ◽

Hepatic Cells ◽

Element Binding Protein ◽

Sterol Regulatory Element

Sterol regulatory element-binding protein-2 (SREBP-2) is a pivotal transcriptional factor in cholesterol metabolism. Factors interfering with the proper functioning of SREBP-2 potentially alter plasma lipid concentrations. Consuming fruits and vegetables is associated with beneficial plasma lipid profile. The mechanism by which plant foods induce desirable lipid changes remains unclear. Apigenin, a common plant food flavonoid, was shown to modulate the nuclear translocation of SREBP-2 in the hepatic cells WRL-68 in the present study. The processing of SREBP-2 protein occurred after translation, and apigenin blocked this activation route. Further examination indicated that AMP-activated protein kinase (AMPK) was activated by the flavone, and co-administrating the AMPK-specific inhibitor compound C could release the blockage. Reporter gene assay revealed that the transactivation of sterol responsive element (SRE)-containing 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) promoter was suppressed by the flavone. Similarly, electromobility shift assay result also demonstrated a reduced DNA-binding activity on the SRE domain under the same treatment. The reduced transactivity and DNA-binding activity could be attributed to a decreased amount of SREBP-2 translocating from cytosol to nucleus as depicted by confocal microscopy. Quantitative RT-PCR assay demonstrated that the transcription of HMGCR followed the same pattern of SREBP-2 translocation. In summary, the present study showed that apigenin prevented SREBP-2 translocation and reduced the downstream gene HMGCR transcription. The minimum effective dosage should be achievable in the form of functional food consumption or dietary supplementation.

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