Disease relevance of SREBF2

• Human prostate cancer cells lack feedback regulation of low-density lipoprotein receptor and its regulator, SREBP2 [1].
• Additionally, these results indicate that mutations or drugs that lower nuclear SREBP-2 would cause hypercholesterolemia [2].
• These results suggest that hypercholesterolemia associated with hypothyroidism can be reversed by agents that directly increase SREBP-2 [2].
• We show here that sterol regulatory element-binding protein 2 (SREBP-2) and its target genes are induced in the adipose tissue of several models of rodent obesity, suggesting cholesterol imbalance in enlarged adipocytes [3].
• Similarly, the mRNA levels for FAS and SREBP-1c in a panel of primary human breast cancer samples showed much greater increases than did those for SREBP-1a and SREBP-2 and were significantly correlated with each other, suggesting coordinate regulation of SREBP-1c and FAS in clinical breast cancer [4].

Psychiatry related information on SREBF2

• This study implied that the variants of SREBF2 might be genetic factors involved in the pathogenesis of vascular dementia [5].

High impact information on SREBF2

• Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment [6].
• In an unbiased search for potential coactivators of SREBP, we isolated a protein of 265 kD from HeLa cells that directly bound SREBP-1 and SREBP-2 [7].
• Sterol-resistant transcription in CHO cells caused by gene rearrangement that truncates SREBP-2 [8].
• Here we trace the defect to a rearrangement in the gene encoding SREBP-2, a membrane-bound transcription factor that regulates cholesterol homeostasis [8].
• SREBP-2 is an 1139-amino acid protein that is bound to extranuclear membranes via a carboxy-terminal attachment domain [8].

Chemical compound and disease context of SREBF2

• Thus, we propose that the decreased LDL receptor and increased serum cholesterol associated with hypothyroidism are secondary to the thyroid hormone effects on SREBP-2 [2].
• Gender-related difference in altered gene expression of a sterol regulatory element binding protein, SREBP-2, by lead nitrate in rats: Correlation with development of hypercholesterolemia [9].
• IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells [10].

Biological context of SREBF2

• The SREBF1 gene mapped to the proximal short arm of chromosome 17 (17p11.2), and the SREBF2 gene was localized to the long arm of chromosome 22 (22q13) [11].
• A perfect 10-bp sterol regulatory element (SRE)-1 sequence was present in the promoter region of SREBF2 [12].
• SREBF2 spans 72 kb and is composed of 19 exons and 18 introns [12].
• The 5'-flanking regions of SREBF2 and of two alternatively spliced forms of SREBF1, SREBF1a and SREBF1c, were sequenced, and the SREBF2 transcription start site was determined [12].
• Sterol regulatory element-binding protein-2 interacts with hepatocyte nuclear factor-4 to enhance sterol isomerase gene expression in hepatocytes [13].

Anatomical context of SREBF2

• The chromosomal locations of human SREBF1 and SREBF2 were determined by analysis of human-rodent somatic cell hybrids and fluorescence in situ hybridization [11].
• Ultrastructural analysis revealed that the punctate foci containing SREBP-2 are electron-dense nuclear bodies, similar or identical to structures containing the promyelocyte (PML) protein [14].
• Insulin and PDGF action could be reconstituted again in these deficient cell lines by reintroducing SREBP-1a or SREBP-2 [15].
• Sterols regulate SREBP-2 mRNA levels in keratinocytes and the epidermis and the proteolytic cleavage of SREBP-2 to the mature active form in keratinocytes [16].
• CHO cells expressing a mutant SREBP-2 with an Asp--> Ala mutation at the CPP32 cleavage site showed sterol-regulated cleavage but no apoptosis-induced cleavage [17].

Associations of SREBF2 with chemical compounds

• Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content [18].
• Insulin-activated Erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding Protein-2 at serine residues 432 and 455 in vivo [19].
• The enzyme cleaved SREBP-1 and SREBP-2 between the Asp and Ser of a conserved sequence (S/DEPDSP) [20].
• Parallel regulation of sterol regulatory element binding protein-2 and the enzymes of cholesterol and fatty acid synthesis but not ceramide synthesis in cultured human keratinocytes and murine epidermis [16].
• SREBP1 and SREBP2 are 47% identical, and they share a novel structure comprising a transcriptionally active NH2-terminal basic helix-loop-helix-leucine zipper (bHLH-Zip) domain followed by a membrane attachment domain [11].

Physical interactions of SREBF2

• Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits its transcriptional activity [21].
• Truncation of SREBP-2 at its COOH terminus prevents the formation of complexes with SCAP and simultaneously reduces proteolytic cleavage [22].
• The results suggest that an increased cellular cholesterol load causes accumulation of SREBP-2 in the smooth endoplasmic reticulum and, therefore, that membrane cholesterol ester may be one signal allowing exit of the SREBP-2/SREBP-cleavage-regulating protein complex to the Golgi [23].

Regulatory relationships of SREBF2

• We found that SREBP-2 inhibited the transcriptional activity of Smad3 in luciferase reporter assays [21].
• Here, we report that glucose deprivation activated ATF6 but suppressed the SREBP2-regulated transcription [24].
• METHODS AND RESULTS: Transient transfections demonstrated that SREBP factors induce Cla-1 promoter activity and that SREBP-2 is a more potent inducer than the SREBP-1a isoform [25].
• Data are presented suggesting that SREBP-2 suppresses the 12 alpha-hydroxylase promoter by interacting with FTF [26].
• Differential effects of sterol regulatory binding proteins 1 and 2 on sterol 12 alpha-hydroxylase. SREBP-2 suppresses the sterol 12 alpha-hydroxylase promoter [26].

Other interactions of SREBF2

• We now demonstrate that SREBP-2 is the predominant SREBP in human keratinocytes and murine epidermis, while SREBP-1 is not detected [16].
• We conclude that SREBP-1a and SREBP-2 mediate different regulatory effects converging at sre-1 and that they appear to be linked to the MAP kinase cascade, possibly being direct substrates of ERK1 and ERK2 [15].
• Immunofluorescence studies suggest that a dynamic interplay exists between PML, as well as another component of the PML-containing nuclear body, SUMO-1, and SREBP-2 within these nuclear structures [14].
• ATF6 modulates SREBP2-mediated lipogenesis [24].
• We investigated the regulation of ABCA1 by SREBP2 in vascular endothelial cells (ECs) [27].

Analytical, diagnostic and therapeutic context of SREBF2

• SREBP-1 68-kDa protein levels were maintained throughout progression, however, SREBP-2 68-kDa protein expression increased after castration and during progression (3-fold) [28].
• The in vitro pull-down and in vivo co-immunoprecipitation experiments showed the direct interaction between SREBP-2 and HNF-4 [13].
• Gel mobility shift assays showed that recombinant SREBP-2-NT protein (1-468) binds to a double-stranded LRP1 DNA fragment (215 to 245) containing a wild-type (wt) SRE sequence but not to a mutated SRE (mt) sequence (5-GAATTCGA-3') [29].
• Chromatin immunoprecipitation assay demonstrated that serum starvation enhanced the association of SREBP2 and the ABCA1 promoter in ECs [27].
• In untreated animals the soluble fragment of SREBP-1, but not of SREBP-2, was detected by immunoblotting of a liver nuclear extract [30].

References