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SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element.

Hua, X, Yokoyama, C, Wu, J, Briggs, M R, Brown, M S, Goldstein, J L, Wang, X·1993·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.90.24.11603
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Abstract

We report the cDNA cloning of SREBP-2, the second member of a family of basic-helix-loop-helix-leucine zipper (bHLH-Zip) transcription factors that recognize sterol regulatory element 1 (SRE-1). SRE-1, a conditional enhancer in the promoters for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A synthase genes, increases transcription in the absence of sterols and is inactivated when sterols accumulate. Human SREBP-2 contains 1141 amino acids and is 47% identical to human SREBP-1a, the first recognized member of this family. The resemblance includes an acidic NH2 terminus, a highly conserved bHLH-Zip motif (71% identical), and an unusually long extension of 740 amino acids on the COOH-terminal side of the bHLH-Zip region. SREBP-2 possesses one feature lacking in SREBP-1a--namely, a glutamine-rich region (27% glutamine over 121 residues). In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. As with SREBP-1a, activation by SREBP-2 occurred in the absence and presence of sterols, abolishing regulation. Cotransfection of low amounts of pSREBP-1a and pSREBP-2 into human embryonic kidney 293 cells stimulated transcription of promoters containing SRE-1 in an additive fashion. At high levels transcription reached a maximum, and the effects were no longer additive. The reason for the existence of two SREBPs and the mechanism by which they are regulated by sterols remain to be determined.

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Crossref · 10.1073/pnas.90.24.11603

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  • SREBP-2 contains an NH2-terminal bHLH-Zip domain that interacts with the SRE in the LDLR gene promoter region, leading to increases in transcription and translation of LDLR protein.

    “SREBP-2 contains a NH2-terminal domain with a basic-helix-loop-helix-leucine zipper (bHLH-Zip)26 that interacts with the SRE in the LDLR gene promotor region27, leading to increases in transcription and translation of LDLR protein.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [27]

    The Abstract (p. 11603) describes an NH2-terminal bHLH-Zip motif, SREBP-2 binding to SRE-1, and activation of SRE-1-containing reporter genes; it identifies SRE-1 as an enhancer in the LDL receptor promoter. It does not report increased translation or levels of LDLR protein, and its transcription result concerns reporter genes rather than a direct measurement of LDLR expression. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • nSREBP-2 can be translocated to the nucleus where it interacts with SRE domains to turn on transcription of target genes, including LDLR.

    “nSREBP-2 can then be translocated to the nucleus where it can interact with SRE domains to turn on transcription of target genes, including LDLR as described above27.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [27]

    The Abstract reports that SREBP-2 binds SRE-1 and activates transcription of reporter genes containing it; it also identifies SRE-1 in the LDL receptor promoter. It does not describe nSREBP-2 translocation to the nucleus or show activation of the endogenous LDLR gene. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • SREBP2 primarily regulates genes linked to cholesterol synthesis and uptake, including HMGCR, SQLE, and LDLR.

    “In contrast, SREBP2 is primarily implicated in the regulation of genes linked to cholesterol synthesis and uptake, including those encoding for the rate-limiting enzymes in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and squalene epoxidase (SQLE), and the low-density lipoprotein receptor (LDLR)6.”

    From Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism (2020) · cites this paper as [6]

    The paper’s available text reports that SREBP-2 binds a sterol regulatory element found in the LDL receptor and HMG-CoA synthase promoters and activates reporters containing that element. It supports a role in cholesterol-related gene regulation, but does not identify HMG-CoA reductase (HMGCR) or squalene epoxidase (SQLE) as targets, or establish that these genes are SREBP-2’s primary regulatory focus. HMG-CoA synthase is not HMGCR. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • SREBP2 is the master transcriptional regulator of the majority of enzymes involved in cholesterol synthesis.

    “SREBP2 is the master transcriptional regulator of the majority of enzymes involved in cholesterol synthesis.”

    From Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol (2021) · cites this paper as [39]

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Citations

Cites

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Research works printed but not linked: 9

  1. Andersson S., Davis D. L., Dahlbäck H., Jörnvall H., Russell D. W. Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem. 1989 May 15;264(14):8222–8229. [PubMed] [Google Scholar]
  2. Briggs M. R., Yokoyama C., Wang X., Brown M. S., Goldstein J. L. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence. J Biol Chem. 1993 Jul 5;268(19):14490–14496. [PubMed] [Google Scholar]
  3. Dawson P. A., Hofmann S. L., van der Westhuyzen D. R., Südhof T. C., Brown M. S., Goldstein J. L. Sterol-dependent repression of low density lipoprotein receptor promoter mediated by 16-base pair sequence adjacent to binding site for transcription factor Sp1. J Biol Chem. 1988 Mar 5;263(7):3372–3379. [PubMed] [Google Scholar]
  4. Don R. H., Cox P. T., Wainwright B. J., Baker K., Mattick J. S. 'Touchdown' PCR to circumvent spurious priming during gene amplification. Nucleic Acids Res. 1991 Jul 25;19(14):4008–4008. doi: 10.1093/nar/19.14.4008. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  5. Ferré-D'Amaré A. R., Prendergast G. C., Ziff E. B., Burley S. K. Recognition by Max of its cognate DNA through a dimeric b/HLH/Z domain. Nature. 1993 May 6;363(6424):38–45. doi: 10.1038/363038a0. [DOI] [PubMed] [Google Scholar] · DOI
  6. Pugh B. F., Tjian R. Mechanism of transcriptional activation by Sp1: evidence for coactivators. Cell. 1990 Jun 29;61(7):1187–1197. doi: 10.1016/0092-8674(90)90683-6. [DOI] [PubMed] [Google Scholar] · DOI
  7. Smith J. R., Osborne T. F., Goldstein J. L., Brown M. S. Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene. J Biol Chem. 1990 Feb 5;265(4):2306–2310. [PubMed] [Google Scholar]
  8. Wang X., Briggs M. R., Hua X., Yokoyama C., Goldstein J. L., Brown M. S. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. II. Purification and characterization. J Biol Chem. 1993 Jul 5;268(19):14497–14504. [PubMed] [Google Scholar]
  9. Yokoyama C., Wang X., Briggs M. R., Admon A., Wu J., Hua X., Goldstein J. L., Brown M. S. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell. 1993 Oct 8;75(1):187–197. [PubMed] [Google Scholar]

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Metadata

Authors
Hua, X., Yokoyama, C., Wu, J., Briggs, M. R., Brown, M. S., Goldstein, J. L., & Wang, X.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1993-12-15
Volume
90
Issue
24
Pages
11603-11607
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.90.24.11603
Cited by
544
References
3
Language
en

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