Growth Hormone Regulates Phosphorylation and Function of CCAAT/Enhancer-binding Protein β by Modulating Akt and Glycogen Synthase Kinase-3

Piwien-Pilipuk, Graciela; Mater, David Van; Ross, Sarah E.; MacDougald, Ormond A.; Schwartz, Jessica

doi:10.1074/jbc.m010193200

Cited by 93 publications

(110 citation statements)

References 57 publications

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“…Site-selective phosphorylation of C/EBP␤ at Ser 105 by protein kinase C enhances C/EBP␤ transactivation activity in HepG2 cells (49). More recently, Piwien-Pilipuk et al (50) have also shown that growth hormone regulates the phosphorylation and function of C/EBP␤ by modulating the PI3K pathway. The results presented here clearly show that activation of the PI3K signaling pathway by expression of the constitutively activated K227E mutant increased neuronal differentiation in cells overexpressing C/EBP␤, whereas activation of this pathway had no effect on parental N2A cells.…”

Section: Discussionmentioning

confidence: 97%

CCAAT/Enhancer-binding Protein β Plays a Regulatory Role in Differentiation and Apoptosis of Neuroblastoma Cells

Cortes‐Canteli¹,

Pignatelli²,

Santos³

et al. 2002

Journal of Biological Chemistry

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The C/EBP␤ (CCAAT/enhancer-binding protein ␤) is a transcription factor that belongs to basic region-leucine zipper class DNA-binding proteins. There is a significant body of evidence that suggests that this protein plays a central role in adipocytic and eosinophilic differentiation. However, there is no information available regarding the role of this transcription factor in the development of mammalian neuronal tissues. In this study, we have examined the effect of C/EBP␤ overexpression on the differentiation and survival of mouse Neuro2A cells. We found that C/EBP␤ induces neuronal differentiation and that this process is inhibited by transfection with the C/EBP homologous protein 10 (CHOP), strongly suggesting that the extension of neurites is indeed due to the C/EBP␤ transcriptional activity. As it has been suggested in adipocyte differentiation, here we show that C/EBP␤ induces the expression of the endogenous C/EBP␣ gene and that this protein by itself is also able to induce a differentiated phenotype in Neuro2A cells. Neuronal differentiation induced by C/EBP␤ requires activation of the phosphatidylinositol 3-kinase signaling pathway, whereas inhibition of the mitogen-activated protein kinase signaling does not have any effect. In addition, we show that C/EBP␤ is expressed in the brain of neonatal rats, suggesting that this protein could play an important role in neuronal maturation. Finally, cell death was also induced by C/EBP␤ through activation of the p53 protein and the cdk inhibitor p21.

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Section: Discussionmentioning

confidence: 97%

CCAAT/Enhancer-binding Protein β Plays a Regulatory Role in Differentiation and Apoptosis of Neuroblastoma Cells

Cortes‐Canteli¹,

Pignatelli²,

Santos³

et al. 2002

Journal of Biological Chemistry

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“…Piwien-Pilipuk et al reported that C/EBP␤ DNA binding is induced by growth hormone (GH) through a dephosphorylation mechanism (27,28). Although the identity of the inhibitory phosphorylated residues was not determined, they suggested that GSK3 may be the relevant kinase.…”

Section: Discussionmentioning

confidence: 99%

RSK-Mediated Phosphorylation in the C/EBPβ Leucine Zipper Regulates DNA Binding, Dimerization, and Growth Arrest Activity

Lee¹,

Shuman²,

Guszczynski

et al. 2010

Molecular and Cellular Biology

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The bZIP transcription factor C/EBP␤ is a target of Ras signaling that has been implicated in Ras-induced transformation and oncogene-induced senescence (OIS). To gain insights into Ras-C/EBP␤ signaling, we investigated C/EBP␤ activation by oncogenic Ras. We show that C/EBP␤ DNA binding is autorepressed and becomes activated by the Ras-Raf-MEK-ERK-p90 RSK cascade. Inducible phosphorylation by RSK on Ser273 in the leucine zipper was required for DNA binding. In addition, three other modifications (phosphorylation on Tyr109 [p-Tyr109], p-Ser111, and monomethylation of Arg114 [me-Arg114]) within an N-terminal autoinhibitory domain were important for Ras-induced C/EBP␤ activation and cytostatic activity. Apart from its role in DNA binding, Ser273 phosphorylation also creates an interhelical g7e salt bridge with Lys268 that increases attractive electrostatic interactions between paired leucine zippers and promotes homodimerization. Mutating Ser273 to Ala or Lys268 to Glu decreased C/EBP␤ homodimer formation, whereas heterodimerization with C/EBP␥ was relatively unaffected. The S273A substitution also reduced the antiproliferative activity of C/EBP␤ in Ras V12 -expressing fibroblasts and decreased binding to target cell cycle genes, while a phosphomimetic substitution (S273D) maintained growth arrest function. Our findings identify four novel C/EBP␤-activating modifications, including RSK-mediated phosphorylation of a bifunctional residue in the leucine zipper that regulates DNA binding and homodimerization and thereby promotes cell cycle arrest.

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“…This leads to a release of the N-terminal transactivation domain (TAD) (11,12) and exchange of interacting Mediator components and activation of the repressed protein (13). Other phosphorylation sites and their corresponding kinases were also identified, including glycogen synthase kinase 3 (GSK-3) that phosphorylates Ser-184 in murine LAP (Ser-33 in LIP) (14); calcium/ calmodulin-dependent protein kinase that phosphorylates Ser-276 (15); and protein kinase C that phosphorylates Ser-105 and Ser-240 and protein kinase A (PKA) that phosphorylates Ser-105, Ser-299, and Ser-240 in LAP (16 -18); p90 ribosomal S kinase (p90rsk) that phosphorylates Ser-105 in rat C/EBP␤ and Thr-217 in murine LAP (19); and Cdk2 and Cdc2 that phosphorylate Ser-64 and Thr-189 in murine C/EBP␤ (20). Several of these phosphorylation events may also depend on each other (21) to modulate the transcriptional activity of C/EBP␤ in response to external stimuli.…”

mentioning

confidence: 99%

G9a-mediated Lysine Methylation Alters the Function of CCAAT/Enhancer-binding Protein-β

Pleß

Kowenz‐Leutz

Knoblich

et al. 2008

Journal of Biological Chemistry

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The functional capacity of the transcriptional regulatory CCAAT/enhancer-binding protein-␤ (C/EBP␤) is governed by protein interactions and post-translational protein modifications. In a proteome-wide interaction screen, the histone-lysine N-methyltransferase, H3 lysine 9-specific 3 (G9a), was found to directly interact with the C/EBP␤ transactivation domain (TAD). Binding between G9a and C/EBP␤ was confirmed by glutathione S-transferase pulldown and co-immunoprecipitation. Metabolic labeling showed that C/EBP␤ is post-translationally modified by methylation in vivo. A conserved lysine residue in the C/EBP␤ TAD served as a substrate for G9a-mediated methylation. G9a, but not a methyltransferase-defective G9a mutant, abrogated the transactivation potential of wild type C/EBP␤. A C/EBP␤ TAD mutant that contained a lysine-toalanine exchange was resistant to G9a-mediated inhibition. Moreover, the same mutation conferred super-activation of a chromatin-embedded, endogenous C/EBP␤ target gene. Our data identify C/EBP␤ as a direct substrate of G9a-mediated post-translational modification that alters the functional properties of C/EBP␤ during gene regulation.

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Growth Hormone Regulates Phosphorylation and Function of CCAAT/Enhancer-binding Protein β by Modulating Akt and Glycogen Synthase Kinase-3

Cited by 93 publications

References 57 publications

CCAAT/Enhancer-binding Protein β Plays a Regulatory Role in Differentiation and Apoptosis of Neuroblastoma Cells

CCAAT/Enhancer-binding Protein β Plays a Regulatory Role in Differentiation and Apoptosis of Neuroblastoma Cells

RSK-Mediated Phosphorylation in the C/EBPβ Leucine Zipper Regulates DNA Binding, Dimerization, and Growth Arrest Activity

G9a-mediated Lysine Methylation Alters the Function of CCAAT/Enhancer-binding Protein-β

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