ERK2-mediated phosphorylation of transcriptional coactivator binding protein PIMT/NCoA6IP at Ser298 augments hepatic gluconeogenesis.

Autor: Kapadia B; Department of Biology, Dr Reddy's Institute of Life Sciences, An Associate Institute of University of Hyderabad, Hyderabad, Andhra Pradesh, India., Viswakarma N; Department of Biology, Dr Reddy's Institute of Life Sciences, An Associate Institute of University of Hyderabad, Hyderabad, Andhra Pradesh, India., Parsa KV; Department of Biology, Dr Reddy's Institute of Life Sciences, An Associate Institute of University of Hyderabad, Hyderabad, Andhra Pradesh, India., Kain V; Department of Biology, Dr Reddy's Institute of Life Sciences, An Associate Institute of University of Hyderabad, Hyderabad, Andhra Pradesh, India., Behera S; Department of Biology, Dr Reddy's Institute of Life Sciences, An Associate Institute of University of Hyderabad, Hyderabad, Andhra Pradesh, India., Suraj SK; Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, Andhra Pradesh, India., Babu PP; Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, Andhra Pradesh, India., Kar A; Department of Life Sciences, Devi Ahilya University, Indore, Madhya Pradesh, India., Panda S; Department of Life Sciences, Devi Ahilya University, Indore, Madhya Pradesh, India., Zhu YJ; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America., Jia Y; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America., Thimmapaya B; Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America., Reddy JK; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America., Misra P; Department of Biology, Dr Reddy's Institute of Life Sciences, An Associate Institute of University of Hyderabad, Hyderabad, Andhra Pradesh, India.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2013 Dec 17; Vol. 8 (12), pp. e83787. Date of Electronic Publication: 2013 Dec 17 (Print Publication: 2013).
DOI: 10.1371/journal.pone.0083787
Abstrakt: PRIP-Interacting protein with methyl transferase domain (PIMT) serves as a molecular bridge between CREB-binding protein (CBP)/ E1A binding protein p300 (Ep300) -anchored histone acetyl transferase and the Mediator complex sub-unit1 (Med1) and modulates nuclear receptor transcription. Here, we report that ERK2 phosphorylates PIMT at Ser(298) and enhances its ability to activate PEPCK promoter. We observed that PIMT is recruited to PEPCK promoter and adenoviral-mediated over-expression of PIMT in rat primary hepatocytes up-regulated expression of gluconeogenic genes including PEPCK. Reporter experiments with phosphomimetic PIMT mutant (PIMT(S298D)) suggested that conformational change may play an important role in PIMT-dependent PEPCK promoter activity. Overexpression of PIMT and Med1 together augmented hepatic glucose output in an additive manner. Importantly, expression of gluconeogenic genes and hepatic glucose output were suppressed in isolated liver specific PIMT knockout mouse hepatocytes. Furthermore, consistent with reporter experiments, PIMT(S298D) but not PIMT(S298A) augmented hepatic glucose output via up-regulating the expression of gluconeogenic genes. Pharmacological blockade of MAPK/ERK pathway using U0126, abolished PIMT/Med1-dependent gluconeogenic program leading to reduced hepatic glucose output. Further, systemic administration of T4 hormone to rats activated ERK1/2 resulting in enhanced PIMT ser(298) phosphorylation. Phosphorylation of PIMT led to its increased binding to the PEPCK promoter, increased PEPCK expression and induction of gluconeogenesis in liver. Thus, ERK2-mediated phosphorylation of PIMT at Ser(298) is essential in hepatic gluconeogenesis, demonstrating an important role of PIMT in the pathogenesis of hyperglycemia.
Databáze: MEDLINE
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