Dual Regulation of Phosphorylation and Dephosphorylation of C/EBPβ Modulate Its Transcriptional Activation and DNA Binding in Response to Growth Hormone

Piwien-Pilipuk, Graciela; MacDougald, Ormond A.; Schwartz, Jessica

doi:10.1074/jbc.m206886200

Cited by 95 publications

(111 citation statements)

References 57 publications

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“…We also observed that hypoxia induced the robust and transient phosphorylation of c/EBP-β at Thr 188 ( Fig. 5B), which is required for efficient function of the transcription activation domain (Piwien-Pilipuk et al, 2002). The decline in c/EBP-β protein levels was insensitive to both salubrinal and AEBSF treatment, suggesting that the mechanisms regulating c/EBP-β expression and/or stability are likely PERK and ATF6 independent.…”

Section: Defining the Role Of Er-stress Responses In Hypoxia-induced mentioning

confidence: 67%

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Halterman

Jesus

Rempe

et al. 2008

Molecular and Cellular Neuroscience

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Understanding the mechanisms governing the switch between hypoxia-induced adaptive and pathological transcription may reveal novel therapeutic targets for stroke. Using an in vitro hypoxia model that temporally separates these divergent responses, we found apoptotic signaling was preceded by a decline in c/EBP-β activity and was associated with markers of ER-stress including transient eIF2α phosphorylation, and the delayed induction of the bZIP proteins ATF4 and CHOP-10. Pretreatment with the eIF2α phosphatase inhibitor salubrinal blocked the activation of caspase-3, indicating that ER-related stress responses are integral to this transition. Delivery of either full-length, or a transcriptionally inactive form of c/EBP-β protected cultures from hypoxic challenge, in part by inducing levels of the anti-apoptotic protein Bcl-2. These data indicate that the pathologic response in cortical neurons induced by hypoxia involves both the loss of c/EBP-β-mediated survival signals and activation of pro-death pathways originating from the endoplasmic reticulum.

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Section: Defining the Role Of Er-stress Responses In Hypoxia-induced mentioning

confidence: 67%

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Halterman

Jesus

Rempe

et al. 2008

Molecular and Cellular Neuroscience

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“…Several studies have found that C/EBP␤ is regulated partly at the level of DNA binding (27,39,40,45), and in vitro experiments using recombinant proteins suggest that N-terminal sequences inhibit the C-terminal bZIP domain (12,47). Here, we show that C/EBP␤ DNA-binding activity in mammalian cells is intrinsically repressed (Lee et al, submitted) and can be activated by oncogenic Ras V12 or growth factors via the Raf/MEK/ERK/RSK pathway.…”

mentioning

confidence: 74%

“…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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“…C/EBP␤ is phosphorylated at multiple sites by stimulation of the mitogen-activated protein kinase cascade and subsequent activation of ribosomal S6 kinase in response to several treatments, including cytokines and growth factors (57)(58)(59)(60). For instance, the phosphorylation on Ser-239 within the nuclear localization signal of murine C/EBP␤ is critical for its nuclear export and inhibition of tumor necrosis factor ␣-stimulated albumin gene transcription in primary mouse hepatocytes (59).…”

Section: Discussionmentioning

confidence: 99%

Pyrrolidine Dithiocarbamate Inhibits Interleukin-6 Signaling through Impaired STAT3 Activation and Association with Transcriptional Coactivators in Hepatocytes

Zhu

Xie

et al. 2006

J. Biol. Chem.

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Dual Regulation of Phosphorylation and Dephosphorylation of C/EBPβ Modulate Its Transcriptional Activation and DNA Binding in Response to Growth Hormone

Cited by 95 publications

References 57 publications

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

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

Pyrrolidine Dithiocarbamate Inhibits Interleukin-6 Signaling through Impaired STAT3 Activation and Association with Transcriptional Coactivators in Hepatocytes

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