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| SREBP1c | |
|---|---|
| Name | Sterol regulatory element-binding protein 1c |
| Alt | SREBP1c |
| Uniprot | P36956 |
| Organism | Human |
| Gene location | 17p11.2 |
SREBP1c SREBP1c is a membrane-bound transcription factor that regulates lipid biosynthesis and energy metabolism. Originally characterized through biochemical studies in the laboratories of investigators associated with Harvard University, Massachusetts Institute of Technology, Cold Spring Harbor Laboratory, National Institutes of Health, and Max Planck Society, SREBP1c has been central to research linking signaling pathways studied at Stanford University, University of Cambridge, Yale University, Johns Hopkins University, and University of California, San Francisco to metabolic disease. Its study intersects with work on enzymes characterized at Rockefeller University, signaling described at University of Oxford, and pharmacology pursued at Novartis, Pfizer, and GlaxoSmithKline.
SREBP1c is synthesized as an inactive precursor anchored in the membranes of the endoplasmic reticulum and nuclear envelope and contains a basic-helix-loop-helix leucine zipper (bHLH-LZ) domain homologous to factors defined at Cold Spring Harbor Laboratory, European Molecular Biology Laboratory, MIT, Caltech, and University of Tokyo. The protein arises from the SREBF1 gene via alternative promoter usage and splicing, producing isoforms that contrast with SREBP1a described in cloning studies from groups at Harvard Medical School, Imperial College London, University of Pennsylvania, UCSF, and University of Toronto. Structural analyses performed using techniques developed at Max Planck Institute for Biophysical Chemistry, European Synchrotron Radiation Facility, Brookhaven National Laboratory, and Argonne National Laboratory revealed the membrane-tethered N-terminal transcription factor and two transmembrane helices conserved across metazoans studied in comparative genomics at Broad Institute, Sanger Institute, Wellcome Trust Centre, Cold Spring Harbor Laboratory, and Erasmus University Rotterdam.
Hepatic expression of SREBP1c is strongly induced by insulin signaling pathways elucidated at Stanford University School of Medicine, University of Cambridge, Yale School of Medicine, Columbia University, and University of Michigan via activation of upstream regulators like Liver X receptor characterized at Institut de Pharmacologie Moléculaire et Cellulaire, Salk Institute, Novartis Institutes for BioMedical Research, ETH Zurich, and University of Basel. Nutrient and hormonal regulation integrates inputs from signaling nodes including mTOR identified at Biozentrum Basel, Dana-Farber Cancer Institute, Cold Spring Harbor Laboratory, University of Pennsylvania, and NIH Clinical Center, as well as feedback from sterol-sensing machinery involving SCAP and INSIG proteins uncovered at Harvard Medical School, Memorial Sloan Kettering Cancer Center, University of Chicago, UCSF, and Massachusetts General Hospital. Post-translational modifications such as phosphorylation by kinases studied at Protein Data Bank, European Molecular Biology Laboratory, Max Planck Institute, Johns Hopkins University, and Karolinska Institute and ubiquitination pathways charted at Rockefeller University, Cold Spring Harbor Laboratory, University of Cambridge, Columbia University, and University of Oxford further modulate SREBP1c stability and activity.
Activated SREBP1c is proteolytically released from membranes by the S1P and S2P proteases characterized in studies at NIH, Max Planck Institute, CNRS, Salk Institute, and University of Tokyo, allowing nuclear translocation and binding to sterol regulatory elements first defined in promoter mapping at Cold Spring Harbor Laboratory, Harvard, Yale, MIT, and Johns Hopkins. In the nucleus, SREBP1c heterodimerizes with partners whose functions were established at EMBL, Wellcome Trust, Caltech, ETH Zurich, and Stanford to recruit chromatin remodelers and coactivators identified at Rockefeller University, Dana-Farber, Broad Institute, Harvard Medical School, and UCSF, thereby upregulating genes encoding enzymes like fatty acid synthase characterized at University of Michigan, Imperial College, University of Cambridge, University of California, and McGill University.
SREBP1c controls hepatic lipogenesis demonstrated in rodent and human studies at Harvard, Yale, NIH, University of Cambridge, and University of Chicago and coordinates triglyceride and phospholipid synthesis linked to lipidomic analyses performed at Broad Institute, Scripps Research Institute, EMBL-EBI, Max Planck Institute for Molecular Cell Biology and Genetics, and University of Texas Southwestern Medical Center. It also influences adipocyte biology investigated at University of Michigan, Columbia University, UT Southwestern, University of Toronto, and University of California San Diego and contributes to developmental programs explored at Wellcome Trust Sanger Institute, Harvard Medical School, Stanford Medicine, Oxford University, and Johns Hopkins.
Aberrant SREBP1c activity is implicated in nonalcoholic fatty liver disease characterized in epidemiological cohorts from Framingham Heart Study, UK Biobank, CDC, World Health Organization, and National Institutes of Health, as well as in insulin resistance and type 2 diabetes studied at Joslin Diabetes Center, Oxford, Harvard Medical School, Mount Sinai, and Mayo Clinic. Genetic and pharmacologic perturbations linking SREBP1c to dyslipidemia were reported by consortia including 1000 Genomes Project, ENIGMA Consortium, GTEx Consortium, International HapMap Project, and Exome Aggregation Consortium and inform risk assessments used by American Heart Association, European Society of Cardiology, World Health Organization, CDC, and National Institutes of Health.
Mouse models with liver-specific manipulation of SREBF1 developed at Jackson Laboratory, Harvard Medical School, MIT, Salk Institute, and European Molecular Biology Laboratory demonstrated effects on steatosis and insulin sensitivity; rat and zebrafish models used at University of Oregon, Scripps Research, Max Planck Institute, University of Cambridge, and Karolinska Institute provided complementary developmental and toxicology data. Cellular systems including hepatocyte lines, adipocyte cultures, and induced pluripotent stem cell–derived tissues studied at Stanford, Broad Institute, Gladstone Institutes, Whitehead Institute, and Salk enabled mechanistic dissection with CRISPR tools pioneered at Broad Institute, MIT, Harvard, UC Berkeley, and Max Planck Institute for Infection Biology.
Strategies to modulate SREBP1c activity via small molecules, antisense oligonucleotides, and nuclear receptor ligands have been pursued by pharmaceutical groups such as Novartis, Pfizer, Roche, GlaxoSmithKline, and AstraZeneca and in academic collaborations at Harvard, Stanford, Yale, NIH, and Karolinska Institute to address nonalcoholic steatohepatitis and dyslipidemia studied in clinical trials registered by FDA, EMA, NIH Clinical Center, European Medicines Agency, and ClinicalTrials.gov. Biomarker development leveraging cohorts from Framingham Heart Study, UK Biobank, All of Us Research Program, NHS, and CDC aims to stratify patients for therapies that target SREBP1c-regulated pathways highlighted in precision-medicine initiatives at Broad Institute, Wellcome Sanger Institute, Massachusetts General Hospital, Stanford Medicine, and Yale School of Medicine.
Category:Transcription factors