Phosphorylation of Serine 256 Suppresses Transactivation by FKHR (FOXO1) by Multiple Mechanisms

Zhang, Xiaohui; Gan, Lixia; Pan, Haiyun; Guo, Shaodong; He, Xiaowei; Olson, Steven T.; Mesecar, Andrew D.; Adam, Stephen A.; Unterman, Terry G.

doi:10.1074/jbc.m208063200

Cited by 279 publications

(273 citation statements)

References 46 publications

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“…Furthermore, impairment of E2F1 nucleocytoplasmic shuttling in undifferentiated keratinocytes significantly increases apoptosis . Nuclear exclusion is an important mechanism to limit the effects of a number of transcription factors on gene expression, and changes in phosphorylation status can regulate their nuclear exit (Zhang et al, 2002). We propose that p38-dependent phosphorylation of S403 and T433 regulates several aspects of E2F1 function in keratinocytes.…”

Section: Discussionmentioning

confidence: 93%

Phosphorylation by p38 MAP kinase is required for E2F1 degradation and keratinocyte differentiation

Dagnino

2008

Oncogene

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The transcription factor E2F1 plays key roles in skin homeostasis, and is essential for normal keratinocyte proliferation and epidermal regeneration after injury. We have previously established that, in differentiating keratinocytes, E2F1 activity is controlled by nuclear export and subsequent degradation. These events are triggered by differentiation-induced stimulation of protein kinase C and p38 mitogen-activated protein kinase (MAPK). However, the mechanisms that induce E2F1 export from the nucleus and the role of p38 MAPK in this process are poorly understood. We now describe a novel regulatory pathway for E2F1, which involves phosphorylation by p38. We demonstrate that E2F1 forms complexes with active p38 through regions that exclude the N-terminus of this transcription factor, and that p38 activity is a major contributor to the phosphorylation status of E2F1 in keratinocytes. Using in vitro kinase assays, we identified Ser403 and Thr433 as the residues phosphorylated by p38. The biological significance of these observations is underscored by the inability of E2F1 mutants lacking one or both of these residues to be exported from the nucleus and degraded when keratinocytes receive differentiation stimuli, which results in impaired keratinocyte maturation.

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Section: Discussionmentioning

confidence: 93%

Phosphorylation by p38 MAP kinase is required for E2F1 degradation and keratinocyte differentiation

Dagnino

2008

Oncogene

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“…⌬256FoxO1 still has two intact Akt phosphorylation sites, Thr 24 and Ser 253 (22). It has been reported that phosphorylation of the first and second Akt phosphorylation sites can affect DNA binding and regulate transcriptional activity of FoxOs (5,36,38,42). Therefore, loss of PDK-1 may enhance DNA binding of ⌬256FoxO1, and ⌬256FoxO1 can inhibit STAT3 binding to Pomc promoter.…”

Section: Discussionmentioning

confidence: 99%

PDK-1/FoxO1 pathway in POMC neurons regulatesPomcexpression and food intake

Iskandar

Cao

Hayashi

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Both insulin and leptin signaling converge on phosphatidylinositol 3-OH kinase [PI( 3 )K]/3-phosphoinositide-dependent protein kinase-1 (PDK-1)/protein kinase B (PKB, also known as Akt) in proopiomelanocortin (POMC) neurons. Forkhead box-containing protein-O1 (FoxO1) is inactivated in a PI( 3 )K-dependent manner. However, the interrelationship between PI( 3 )K/PDK-1/Akt and FoxO1, and the chronic effects of the overexpression of FoxO1 in POMC neurons on energy homeostasis has not been elucidated. To determine the extent to which PDK-1 and FoxO1 signaling in POMC neurons was responsible for energy homeostasis, we generated POMC neuron-specific Pdk1 knockout mice ( POMCPdk1−/−) and mice selectively expressing a constitutively nuclear (CN)FoxO1 or transactivation-defective (Δ256)FoxO1 in POMC neurons ( CNFoxO1 POMC or Δ256FoxO1 POMC). POMCPdk1−/− mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1 POMC mice exhibited mild obesity and hyperphagia compared with POMCPdk1−/− mice. Although expression of the CNFoxO1 made POMCPdk1−/− mice more obese due to excessive suppression of Pomc gene, overexpression of Δ256FoxO1 in POMC neurons had no effects on metabolic phenotypes and Pomc expression levels of POMCPdk1−/− mice. These data suggest a requirement for PDK-1 and FoxO1 in transcriptional regulation of Pomc and food intake.

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“…Multiple sites for both phosphorylation and acetylation have been identified within the FOXO1 protein (54). The Ab used in this study is specific for Ser 256 , a site phosphorylated by Akt (55). Btk may regulate phosphorylation at other sites that would not be detected with this reagent.…”

Section: Discussionmentioning

confidence: 99%

B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase

Hinman

Bushanam

Nichols

et al. 2007

The Journal of Immunology

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BCR cross-linking promotes mature B cell proliferation and survival. PI3K-mediated down-regulation of proapoptotic and antimitogenic genes such as forkhead box transcription factor class O 1 (FOXO1) is an important component of this process. Previously, BCR-induced phosphorylation of FOXO1 was shown to lead to a block in nuclear localization and subsequent protein degradation. We demonstrate that the BCR also signals through PI3K to down-regulate FOXO1 mRNA expression. Bruton’s tyrosine kinase (Btk), a downstream effector of PI3K, signals through B cell linker protein (BLNK) and phospholipase C (PLC)γ2 to mediate B cell proliferation and survival in response to BCR cross-linking. BCR-induced down-regulation of FOXO1 mRNA was impaired in murine knockouts of Btk, BLNK, and PLCγ2. Because B cells in these models are predominantly immature, experiments were also performed using mature B cells expressing low levels of Btk and BLNK. Similar results were obtained. Inhibitors of downstream components of the Btk/BLNK/PLCγ2 pathway were used to define the mechanism by which Btk signaling inhibits FOXO1 expression. The protein kinase Cβ inhibitor Gö6850 had minimal effects on BCR-mediated FOXO1 mRNA down-regulation. However, cyclosporin A, an inhibitor of the Ca2+-dependent phosphatase calcineurin, had similar effects on FOXO1 mRNA expression as the PI3K inhibitor LY294002. Neither Btk deficiency nor cyclosporin A prevented FOXO1 protein phosphorylation, indicating that PI3K down-regulates FOXO1 via two independent pathways. We show that the Btk/BLNK/PLCγ2 pathway mediates BCR-induced changes in expression of the FOXO1 target gene cyclin G2. These observations support the hypothesis that Btk mediates BCR-induced proliferation and survival in part via inhibition of FOXO expression.

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Phosphorylation of Serine 256 Suppresses Transactivation by FKHR (FOXO1) by Multiple Mechanisms

Cited by 279 publications

References 46 publications

Phosphorylation by p38 MAP kinase is required for E2F1 degradation and keratinocyte differentiation

Phosphorylation by p38 MAP kinase is required for E2F1 degradation and keratinocyte differentiation

PDK-1/FoxO1 pathway in POMC neurons regulatesPomcexpression and food intake

B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase

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