p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation

Rampalli, Shravanti; Li, LiFang; Mak, Esther; Ge, Kai; Brand, Marjorie; Tapscott, Stephen J.; Dilworth, F. Jeffrey

doi:10.1038/nsmb1316

Cited by 192 publications

(223 citation statements)

References 41 publications

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“…This is consistent with the concept that E2F1 phosphorylation by p38, together with its export from the nucleus and degradation, is essential for proper keratinocyte differentiation. In this regard, p38 also plays a positive regulatory role in muscle differentiation, through phosphorylation and modulation of the Mef2 transcription factor (Rampalli et al, 2007), suggesting that p38 activity most likely plays a broad role in differentiation in a variety of tissues.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

Dagnino

2008

Oncogene

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“…pathway through upregulation of the JNK phosphatase MKP-1 [25]. More recently, p38 has been linked to the epigenetic regulation of myogenesis through both repressive [26,27] and activating [28] histone modifications. p38c acts in opposition to p38a, blocking premature differentiation through induction of a repressive MyoD transcriptional complex [26].…”

Section: Introductionmentioning

confidence: 99%

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

et al. 2013

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Stem cell function is essential for the maintenance of adult tissue homeostasis. Controlling the balance between selfrenewal and differentiation is crucial to maintain a receptive satellite cell pool capable of responding to growth and regeneration cues. The mitogen-activated protein kinase p38a has been implicated in the regulation of these processes but its influence in adult muscle remains unknown. Using conditional satellite cell p38a knockout mice we have demonstrated that p38a restricts excess proliferation in the postnatal growth phase while promoting timely myoblast differentiation. Differentiation was still able to occur in the p38a-null satellite cells, however, but was delayed. An absence of p38a resulted in a postnatal growth defect along with the persistence of an increased reservoir of satellite cells into adulthood. This population was still capable of responding to cardiotoxin-induced injury, resulting in complete, albeit delayed, regeneration, with further enhancement of the satellite cell population. Increased p38c phosphorylation accompanied the absence of p38a, and inhibition of p38c ex vivo substantially decreased the myogenic defect. We have used genomewide transcriptome analysis to characterize the changes in expression that occur between resting and regenerating muscle, and the influence p38a has on these expression profiles. This study provides novel evidence for the fundamental role of p38a in adult muscle homeostasis in vivo.

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“…Furthermore, MyoD binding does not always correlate with transcriptional activation (9,15). MyoD, with the help of other transcription factors and/or cofactors, can bind to E-box sites prior to transcriptional activation (25,26). Recently, it was shown that MyoD binds to many of the skeletal muscle-specific genes during the course of differentiation (24).…”

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confidence: 99%

MyoD Directly Up-regulates Premyogenic Mesoderm Factors during Induction of Skeletal Myogenesis in Stem Cells

Gianakopoulos

Mehta

Voronova

et al. 2011

Journal of Biological Chemistry

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Gain-and loss-of-function experiments have illustrated that the family of myogenic regulatory factors is necessary and sufficient for the formation of skeletal muscle. Furthermore, MyoD required cellular aggregation to induce myogenesis in P19 embryonal carcinoma stem cells. To determine the mechanism by which stem cells can be directed into skeletal muscle, a time course of P19 cell differentiation was examined in the presence and absence of exogenous MyoD. By quantitative PCR, the first MyoD up-regulated transcripts were the premyogenic mesoderm factors Meox1, Pax7, Six1, and Eya2 on day 4 of differentiation. Subsequently, the myoblast markers myogenin, MEF2C, and Myf5 were up-regulated, leading to skeletal myogenesis. These results were corroborated by Western blot analysis, showing up-regulation of Pax3, Six1, and MEF2C proteins, prior to myogenin protein expression. To determine at what stage a dominant-negative MyoD/EnR mutant could inhibit myogenesis, stable cell lines were created and examined. Interestingly, the premyogenic mesoderm factors, Meox1, Pax3/7, Six1, Eya2, and Foxc1, were down-regulated, and as expected, skeletal myogenesis was abolished. Finally, to identify direct targets of MyoD in this system, chromatin immunoprecipitation experiments were performed. MyoD was observed associated with regulatory regions of Meox1, Pax3/7, Six1, Eya2, and myogenin genes. Taken together, MyoD directs stem cells into the skeletal muscle lineage by binding and activating the expression of premyogenic mesoderm genes, prior to activating myoblast genes.

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p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation

Cited by 192 publications

References 41 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

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

MyoD Directly Up-regulates Premyogenic Mesoderm Factors during Induction of Skeletal Myogenesis in Stem Cells

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