PKCε Stimulated Arginine Methylation of RIP140 for Its Nuclear-Cytoplasmic Export in Adipocyte Differentiation

Gupta, Pawan; Huq, M. D. Mostaqul; Khan, Amjad Ali; Tsai, Nien Pei; Li, Wei

doi:10.1371/journal.pone.0002658

Cited by 33 publications

(51 citation statements)

References 47 publications

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“…Purity and enrichment of nuclear fractions were demonstrated by measuring nuclear protein lamin A/C and the cytosolic protein ␤ -tubulin (T5201; Sigma-Aldrich) as previously described ( 28 ).…”

Section: Nuclear and Cytoplasmic Fractions And Brca1 Immunoblottingmentioning

confidence: 99%

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BRCA1 is a novel regulator of metabolic function in skeletal muscle

Jackson

Gidlund

Norrbom

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org breast cancer and/or tumorigenesis in reproductive tissues ( 3 ). The BRCA1 gene produces either a full-length breast cancer type 1 susceptibility protein (BRCA1) or through alternatively splicing two documented variants, BRCA1 ⌬ 11 or BRCA1 ⌬ 11b, both of which lack a nuclear localization signal ( 4 ). Recently, BRCA1 was identifi ed as a regulator of lipid metabolism in human breast cancer cells (MCF7) as a result of direct interaction with the phosphorylated form of acetylCoA carboxylase (ACC-p) at the BRCA1 C-terminal (BRCT) domains ( 5, 6 ). The interaction encourages the maintenance of the phosphorylated state of ACC thereby altering lipid metabolism in the cancer cell line ( 5, 6 ).ACC has two isoforms, ACC1 or ACC2, with ACC2 containing an extra 146 amino acids in the NH 2 -terminal region. ACC activity is negatively regulated by phosphorylation of residue Ser 79 on ACC1 and Ser 221 on ACC2 ( 7,8 ). In the active form (i.e., dephosphorylated), ACC catalyzes the carboxylation of acetyl-CoA into malonyl-CoA (MaCoA). Changes in cellular MaCoA content alter intracellular lipid dynamics in two specifi c manners ( 9, 10 ). MaCoA directly contributes to de novo synthesis of palmitate via FAS and MaCoA also allosterically inhibits carnitine palmitoyltransferase-1 (CPT-1), a mitochondrial long chain fatty acid transporter ( 11 ). Thus, in mammary tissue the ability of BRCA1 to affect ACC activity alters cellular lipid concentrations by indirectly regulating rates of fatty acid synthesis and/or the fl ux of fatty acids into the mitochondria.Abstract Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to defi ne a functional role for BRCA1 in skeletal muscle using a translational approach. For the fi rst time in both mice and humans, we identifi ed the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases. -Jackson, K. C., E-K. Gidlund, J. Abbreviations: ACC, acetyl-CoA carboxylase; ACC-p, phosphorylated form of acetyl-CoA carboxylase; AICAR, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide; AMPK, AMP-activated protein kinase; BRCA1, Breast Cancer 1, early onset; BRCA1 MG KO, mammary gland tissue fr...

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Section: Nuclear and Cytoplasmic Fractions And Brca1 Immunoblottingmentioning

confidence: 99%

“…The mean (range) age, height, and weight were 26 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) years, 177 (158-190) cm, and 75 (58-90) kg, respectively. The mean (range) maximal oxygen consumption (VO 2 max) was 48 ml·kg Ϫ 1 ·min Ϫ 1 .…”

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confidence: 99%

BRCA1 is a novel regulator of metabolic function in skeletal muscle

Jackson

Gidlund

Norrbom

et al. 2014

Journal of Lipid Research

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“…The immunoprecipitates were subjected to immunoblotting with anti-methyl-arginine (Me-R) antibody, which specifically recognizes methylated arginine residues (Gupta et al, 2008). As shown in Figure 3a, anti-methyl-arginine antibody detected more methylated Axin from HEK293T than shPRMT1-treated cell lysates.…”

Section: Prmt1 Methylates Axin In Vivomentioning

confidence: 99%

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

Cha

Kim

et al. 2011

Oncogene

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Axin, a negative regulator of Wnt signaling, is a key scaffold protein for the b-catenin destruction complex. It has been previously shown that multiple post-translational modification enzymes regulate the level of Axin. Here, we provide evidence that protein arginine methyltransferase 1 (PRMT1) directly interacts with and methylates the 378th arginine residue of Axin both in vitro and in vivo. We found that the transient expression of PRMT1 led to an increased level of Axin and that knockdown of endogenous PRMT1 by short hairpin RNA reduced the level of Axin. These results suggest that methylation by PRMT1 enhanced the stability of Axin. Methylation of Axin by PRMT1 also seemingly enhanced the interaction between Axin and glycogen synthase kinase 3b, leading to decreased ubiquitination of Axin. Consistent with the role of PRMT1 in the regulation of Axin, knockdown of PRMT1 enhanced the level of cytoplasmic b-catenin as well as b-catenin-dependent transcription activity. In summary, we show that the methylation of Axin occurred in vivo and controlled the stability of Axin. Therefore, methylation of Axin by PRMT1 may serve as a finely tuned regulation mechanism for Wnt/b-catenin signaling.

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“…On the other hand, RIP140 methylation by protein arginine N-methyltransferase-1 (PRMT1) leads to RIP140 nuclear export and inhibition of its trans-repressive properties (21), suggesting that RIP140 relocalization into the cytoplasm blocks its capability to act as a transcriptional corepressor. Interestingly, nuclear export of RIP140 has been shown to be triggered by its phosphorylation by PKCε followed by arginine methylation in adipocytes (12). When phosphorylation-deficient RIP140 was reintroduced into RIP140-null adipocytes, the defect in fat accumulation was rescued (12).…”

Section: Regulation Of Rip140 Activitymentioning

confidence: 99%

“…Interestingly, nuclear export of RIP140 has been shown to be triggered by its phosphorylation by PKCε followed by arginine methylation in adipocytes (12). When phosphorylation-deficient RIP140 was reintroduced into RIP140-null adipocytes, the defect in fat accumulation was rescued (12). Thus, cytoplasmic localization of RIP140 can be seen as a supplementary mechanism to move RIP140 away from target promoters and enables the expression of genes implicated in fatty acid oxidation.…”

Section: Regulation Of Rip140 Activitymentioning

confidence: 99%

The metabolic coregulator RIP140: an update

Fritah

Christian

Parker

2010

American Journal of Physiology-Endocrinology and Metabolism

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Fritah A, Christian M, Parker MG. The metabolic coregulator RIP140: an update. Am J Physiol Endocrinol Metab 299: E335-E340, 2010. First published June 8, 2010 doi:10.1152/ajpendo.00243.2010.-RIP140 is a transcriptional coregulator highly expressed in metabolic tissues where it has important and diverse actions. RIP140-null mice show that it plays a crucial role in the control of lipid metabolism in adipose tissue, skeletal muscle, and the liver and is essential for female fertility. RIP140 has been shown to act as a ligand-dependent transcriptional corepressor for metabolic nuclear receptors such as estrogen-related receptors and peroxisome proliferator-activated receptors. The role of RIP140 as a corepressor has been strengthened by the characterization of RIP140-overexpressing mice, although it emerges through several studies that RIP140 can also behave as a coactivator. Nuclear localization of RIP140 is important for controlling transcription of target genes and is subject to regulation by posttranslational modifications. However, cytoplasmic RIP140 has been shown to play a role in the control of metabolism through direct regulation of glucose transport in adipocytes. In this review, we focus on recent advances highlighting the growing importance of RIP140 as a regulator of energy homeostasis.

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PKCε Stimulated Arginine Methylation of RIP140 for Its Nuclear-Cytoplasmic Export in Adipocyte Differentiation

Cited by 33 publications

References 47 publications

BRCA1 is a novel regulator of metabolic function in skeletal muscle

BRCA1 is a novel regulator of metabolic function in skeletal muscle

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

The metabolic coregulator RIP140: an update

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