Diversity and specificity of the mitogen-activated protein kinase phosphatase-1 functions

Lawan, Ahmed; Shi, Hao; Gatzke, Florian; Bennett, Anton M.

doi:10.1007/s00018-012-1041-2

Cited by 70 publications

(63 citation statements)

References 132 publications

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“…1), which represent the genes used in all subsequent analyses. Dual-specificity phosphatase 1 (DUSP1), also identified as MAPK phosphatase-1, a well-known inhibitor of the MAPK pathway (18), was significantly upregulated. Other highly significant upregulated genes included the Ras homolog family member B (RHOB), growth arrest and DNA-damage-inducible beta (GADD45B), and the regulator of G-protein signaling 1 (RGS1).…”

Section: Statin Treatment-induced Gene Expression Alterations In Pairmentioning

confidence: 99%

Global Transcriptional Changes Following Statin Treatment in Breast Cancer

Bjarnadottir

Kimbung

Johansson

et al. 2015

Clinical Cancer Research

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Background: Statins purportedly exert antitumoral effects, but the underlying mechanisms are currently not fully elucidated. The aim of this study was to explore potential statininduced effects on global gene expression profiles in primary breast cancer.Experimental Design: This window-of-opportunity phase II trial enrolled 50 newly diagnosed breast cancer patients prescribed atorvastatin (80 mg/day) for 2 weeks presurgically. Preand posttreatment tumor samples were analyzed using Significance Analysis of Microarrays (SAM) to identify differentially expressed genes. Similarly, SAM and gene ontology analyses were applied to gene expression data derived from atorvastatintreated breast cancer cell lines (MCF7, BT474, SKBR3, and MDAMB231) comparing treated and untreated cells. The Systematic Motif Analysis Retrieval Tool (SMART) was used to identify enriched transcription factor-binding sites. Literature Vector Analysis (LitVAn) identified gene module functionality,

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Section: Statin Treatment-induced Gene Expression Alterations In Pairmentioning

confidence: 99%

Global Transcriptional Changes Following Statin Treatment in Breast Cancer

Bjarnadottir

Kimbung

Johansson

et al. 2015

Clinical Cancer Research

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“…One mechanism likely involves the coordinated inactivation of the promyogenic MAPKs by the MAPK phosphatases (MKPs). The MKPs constitute a family of 10 dual-specificity phosphatases (DUSPs) that exhibit the capacity to specifically dephosphorylate MAPKs on the regulatory threonine and tyrosine residues (33)(34)(35)(36). However, the identity of the physiologically relevant MKP that inactivates the promyogenic MAPKs in SCs, and then curtails regenerative myogenesis, has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5

et al. 2013

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“…MAPK activity is opposed by specific dephosphorylation through the actions of MAPK phosphatases (MKPs) (13). The MKPs have been demonstrated to play a variety of roles in metabolic homeostasis (14).…”

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confidence: 99%

Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

Lawan

Zhang

Gatzke

et al. 2015

Molecular and Cellular Biology

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The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH 2 -terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis. O besity is a major problem globally, and its incidence is increasing at an alarming rate (1). Obesity predisposes to the development of nonalcoholic fatty liver disease (NAFLD), which is a spectrum of liver-related pathologies that encompasses steatosis, nonalcoholic steatosis, and nonalcoholic steatohepatitis (2). The development of hepatosteatosis arises as a result of an imbalance between triglyceride deposition and removal. Epidemiologically, NAFLD is associated with type 2 diabetes, suggesting that hepatosteatosis and the development of insulin resistance are causally linked (2). However, both genetic mouse models and clinical data suggest dissociation of hepatosteatosis from insulin resistance, arguing against the existence of such a causal link (3). Several proposed mechanisms have been put forth to explain the relationship between hepatosteatosis and insulin resistance. One mechanism proposes that type 2 diabetes results in hyperinsulinemia, which promotes hepatic lipogenesis and thus hepatosteatosis. Dysfunction in hepatic lipid metabolism and lipotoxicity have also been proposed to activate serine/threonine kinases that subsequently lead to the failure of insulin to signal (4).The actions of kinases in physiological and pathophysiological metabolic pathways have been studied extensively (5, 6). In particular, the mitogen-activated protein kinase (MAPK) pathway is an established regulator of hepatic metabolism (7-10). The stressresponsive MAPK c-Jun NH 2 -terminal kinase 1 (JNK1), when deleted specifically in the liver, results in the development of hepatosteatosis, enhanced hepatic glucose produ...

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Diversity and specificity of the mitogen-activated protein kinase phosphatase-1 functions

Cited by 70 publications

References 132 publications

Global Transcriptional Changes Following Statin Treatment in Breast Cancer

Global Transcriptional Changes Following Statin Treatment in Breast Cancer

Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5

Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

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