Modulating nuclear receptor function: may the phos be with you

Shao, Dalei; Lazar, Mitchell A.

doi:10.1172/jci7421

Cited by 115 publications

(94 citation statements)

References 28 publications

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“…37), enhanced recruitment of cofactors (38 -40), reduced affinity for ligand (33), increased or decreased capacity for DNA binding (reviewed in Ref. 37), enhanced or inhibited heterodimerization (41,42), and susceptibility to proteosomal degradation (43). Our results indicate that p38 MAPK-mediated phosphorylation of PPAR␣ leads to an increase in ligand-dependent transactivating function.…”

Section: P38 Mapk-mediated Activation Of Ppar␣ Maps To Phosphorylatiomentioning

confidence: 63%

“…p38 Activates PPAR␣A diverse array of molecular consequences have been attributed to nuclear receptor phosphorylation, including increased or decreased ligand-dependent and ligand-independent activation (reviewed in Ref. 37), enhanced recruitment of cofactors (38 -40), reduced affinity for ligand (33), increased or decreased capacity for DNA binding (reviewed in Ref. 37), enhanced or inhibited heterodimerization (41,42), and susceptibility to proteosomal degradation (43).…”

Section: P38 Mapk-mediated Activation Of Ppar␣ Maps To Phosphorylatiomentioning

confidence: 99%

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p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

Barger

Browning

Garner

et al. 2001

Journal of Biological Chemistry

243

161

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The expression of enzymes involved in fatty acid ␤-oxidation (FAO), the principal source of energy production in the adult mammalian heart, is controlled at the transcriptional level via the nuclear receptor peroxisome proliferator-activated receptor ␣ (PPAR␣). Evidence has emerged that PPAR␣ activity is activated as a component of an energy metabolic stress response. The p38 mitogen-activated protein kinase (MAPK) pathway is activated by cellular stressors in the heart, including ischemia, hypoxia, and hypertrophic growth stimuli. We show here that PPAR␣ is phosphorylated in response to stress stimuli in rat neonatal cardiac myocytes; in vitro kinase assays demonstrated that p38 MAPK phosphorylates serine residues located within the NH 2 -terminal A/B domain of the protein. Transient transfection studies in cardiac myocytes and in CV-1 cells utilizing homologous and heterologous PPAR␣ target element reporters and mammalian one-hybrid transcription assays revealed that p38 MAPK phosphorylation of PPAR␣ significantly enhanced ligand-dependent transactivation. Cotransfection studies performed with several known coactivators of PPAR␣ demonstrated that p38 MAPK markedly increased coactivation specifically by PGC-1, a transcriptional coactivator implicated in myocyte energy metabolic gene regulation and mitochondrial biogenesis. These results identify PPAR␣ as a downstream effector of p38 kinase-dependent stress-activated signaling in the heart, linking extracellular stressors to alterations in energy metabolic gene expression.The expression of enzymes involved in fatty acid ␤-oxidation (FAO), 1 the principal source of energy production in the adult mammalian heart, is tightly controlled at the transcriptional level during cardiac development and in response to physiologic and pathophysiologic stimuli (1-7). The nuclear receptor PPAR␣ has been shown to serve as a key transcriptional regulator of this energy metabolic pathway (Ref. 8; reviewed in Ref. 9). PPAR␣ is a member of the nuclear receptor superfamily of transcription factors and binds cognate response elements as an obligate heterodimer with the retinoid X receptor (RXR). PPAR␣ is ligand-activated by a variety of natural and synthetic agonists, including arachidonic acid derivatives, fibrates, and long-chain fatty acids: metabolic substrates for cardiac FAO enzymes. The important role played by PPAR␣ in cardiac metabolism is underscored by the marked reduction in the basal level of cardiac FAO enzyme gene expression in PPAR␣ Ϫ/Ϫ mice (10, 11), leading to reduced long-chain fatty acid uptake and oxidation (12).Evidence has emerged that PPAR␣ plays a critical role in the energy metabolic stress response in tissues that rely largely on mitochondrial fat oxidation for energy production, such as heart and liver. Under normal physiologic conditions, the expression of cardiac FAO enzyme genes are induced after a short term fast coincident with increased use of fatty acids for myocardial energy production (1, 3). In contrast, PPAR␣ Ϫ/Ϫ mice do not exhibit the expecte...

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Section: P38 Mapk-mediated Activation Of Ppar␣ Maps To Phosphorylatiomentioning

confidence: 63%

Section: P38 Mapk-mediated Activation Of Ppar␣ Maps To Phosphorylatiomentioning

confidence: 99%

p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

Barger

Browning

Garner

et al. 2001

Journal of Biological Chemistry

243

161

View full text Add to dashboard Cite

show abstract

“…The presence of nuclear localization signals on adipogenic transcription factors have been described in some detail for C/EBP (56) and CREB (57), and they have been inferred from large deletions for PGC-1␣ (58) and a mutation forming a truncated PPAR␣ (59); however, there have been no reports indicating that a change in nuclear localization is a mechanism for regulating adipogenesis. In addition, phosphorylation is a common mechanism associated with the regulation of nuclear translocation, and although phosphorylation occurs on adipogenic transcription factors (58,60,61), the function of phosphorylation in the control of adipogenesis is not well understood (62), nor has it been previously associated with mechanisms of nuclear translocation.…”

Section: Fig 7 Nuclear Translocation Of Pka and Nf-bmentioning

confidence: 99%

Sequestration of Thermogenic Transcription Factors in the Cytoplasm during Development of Brown Adipose Tissue

Rim

Xue

Gawrońska‐Kozak

et al. 2004

Journal of Biological Chemistry

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Transcription factors that regulate gene expression during adipogenesis also control the expression of genes of thermogenesis in brown adipose tissue, in particular, the mitochondrial uncoupling protein gene (Ucp1). There is evidence that a plasticity exists among adipocytes in which activation of the Ucp1 gene together with mitochondrial biogenesis can increase the brown adipocyte character of white fat. To understand this process, we have characterized the changes in transcription that occur in interscapular brown adipocytes during development. We have found dramatic reductions in both DNA-binding activity to probes and immunoreactive protein for peroxisome proliferator-activated receptor, retinoid X receptor, CCAAT/enhancer binding protein, and cAMP-response element-binding protein regulatory motifs in nuclear extracts when mice reach adulthood. Exposure of adult mice to the cold, which reactivates Ucp1 expression, leads to a re-accumulation of factors in the nucleus. We propose that transcription factors are sequestered in the cytoplasm as mice age under conditions of reduced thermogenesis. Changes in isoform subtypes for peroxisome proliferator-activated receptor-␥ and cAMP-response element-binding proteins indicate an additional level of control on gene expression during thermogenesis. The increased movement of the RII␤ protein kinase A regulatory subunit into the nucleus with age suggests a mechanism for regulating the phosphorylation of transcription factors in the nucleus in response to the thermogenic requirements of the animal. Nuclear factor-B has been used as a model to demonstrate that the nuclear localization of transcription factors in brown fat are reduced during post-natal development. Furthermore, it was found by immunofluorescence that adrenergic stimulation of primary adipocyte cultures causes an increase of both the protein kinase A catalytic ␣-subunit and nuclear factor-B into the nucleus.

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“…Phosphorylation sites at serine 104 (and/or 106), serine 118 and serine 167 modulate AF-1 activity (Ali et al, 1993b;Arnold et al, 1994;Le Go et al, 1994;Shao and Lazar, 1999;Smith, 1998). Much interest has been generated by the ®nding that S118 can be phosphorylated by MAPK in vitro and by activation of the MAPK signal transduction pathway in vivo.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of human estrogen receptor α at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera

et al. 2002

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Estrogen receptor a (ERa) is a transcription factor that regulates expression of target genes in a ligand-dependent manner. Activation of gene expression is mediated by two transcription activation functions AF-1 and AF-2, which act in a promoter-and cell-speci®c manner. Whilst AF-2 activity is regulated by estrogen (E2) binding, the activity of AF-1 is additionally modulated by phosphorylation at several sites. One of these phosphorylation sites, serine 118 (S118) is of particular interest as its mutation signi®cantly reduces ERa activity. Previous studies have shown that S118 can be phosphorylated by the ERK1/2 mitogen activated protein kinases (MAPK) and by the cyclindependent protein kinase Cdk7. In this study we use antisera that speci®cally recognize ERa phosphorylated at S118 to demonstrate that MAPK phosphorylates S118 in a ligand-independent manner, whereas Cdk7 mediates E2-induced phosphorylation of S118. E2 stimulation of S118 phosphorylation was observed within 10 min of its addition and was maximal at 10 77 M E2. S118 phosphorylation was maximal at 30 min but then declined, such that by 180 min following E2 addition little S118 phosphorylation was evident. S118 phosphorylation was also induced by the partial estrogen antagonist 4-hydroxytamoxifen, but not by the complete antagonist ICI 182, 780. S118 phosphorylation upon addition of the MAPK inducers EGF or PMA followed the expected time courses. Finally, we show that ERa is phosphorylated at S118 in vivo using immunoblotting of extracts prepared from a series of ERa-positive breast tumours.

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Modulating nuclear receptor function: may the phos be with you

Cited by 115 publications

References 28 publications

p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

Sequestration of Thermogenic Transcription Factors in the Cytoplasm during Development of Brown Adipose Tissue

Phosphorylation of human estrogen receptor α at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera

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