Journal article
Protein phosphatase 2A (PP2A) regulates low density lipoprotein uptake through regulating sterol response element-binding protein-2 (SREBP-2) DNA binding
The Journal of biological chemistry, v 289(24), pp 17268-17279
13 Jun 2014
PMID: 24770487
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
LDL-cholesterol (LDL-C) uptake by Ldlr is regulated at the transcriptional level by the cleavage-dependent activation of membrane-associated sterol response element-binding protein (SREBP-2). Activated SREBP-2 translocates to the nucleus, where it binds to an LDLR promoter sterol response element (SRE), increasing LDLR gene expression and LDL-C uptake. SREBP-2 cleavage and translocation steps are well established. Several SREBP-2 phosphorylation sites have been mapped and functionally characterized. The phosphatases dephosphorylating these sites remain elusive. The phosphatase(s) regulating SREBP-2 represents a novel pharmacological target for treating hypercholesterolemia. Here we show that protein phosphatase 2A (PP2A) promotes SREBP-2 LDLR promoter binding in response to cholesterol depletion. No binding to an LDLR SRE was observed in the presence of the HMG-CoA reductase inhibitor, lovastatin, when PP2A activity was inhibited by okadaic acid or depleted by siRNA methods. SREBP-2 cleavage and nuclear translocation were not affected by loss of PP2A. PP2A activity was required for SREBP-2 DNA binding. In response to cholesterol depletion, PP2A directly interacted with SREBP-2 and altered its phosphorylation state, causing an increase in SREBP-2 binding to an LDLR SRE site. Increased binding resulted in induced LDLR gene expression and increased LDL uptake. We conclude that PP2A activity regulates cholesterol homeostasis and LDL-C uptake.
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Details
- Title
- Protein phosphatase 2A (PP2A) regulates low density lipoprotein uptake through regulating sterol response element-binding protein-2 (SREBP-2) DNA binding
- Creators
- Lyndi M Rice - From the Oncoveda Cancer Institute andMelissa Donigan - the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 andMuhua Yang - the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 andWeidong Liu - the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 andDevanshi Pandya - the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 andBiny K Joseph - the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 andValerie Sodi - From the Oncoveda Cancer Institute andTricia L Gearhart - the Department of Molecular Biology and Biochemistry, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129Jenny Yip - the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 andMichael Bouchard - the Department of Molecular Biology and Biochemistry, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129Joseph T Nickels, Jr - the Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey 08691 and jnickels@venenumbiodesign.com
- Publication Details
- The Journal of biological chemistry, v 289(24), pp 17268-17279
- Publisher
- ASBMB Publications / Elsevier; United States
- Grant note
- P30 CA056036 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000338016200058
- Scopus ID
- 2-s2.0-84902439487
- Other Identifier
- 991014877655604721
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- Web of Science research areas
- Biochemistry & Molecular Biology