CLP-1 associates with MyoD and HDAC to restore skeletal muscle cell regeneration

Galatioto, Josephine; Mascareno, Eduardo; Siddiqui, M.A.Q.

doi:10.1242/jcs.073387

Cited by 17 publications

(15 citation statements)

References 30 publications

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“…P-TEFb has been reported to regulate the function of key myogenic transcription factors MyoD and MEF2 (32)(33)(34), while P-TEFb activity is globally suppressed in most adult stem cells, including satellite cells, due to their low demand of mRNA synthesis (35). We have previously shown that haplodeficiency of Hexim1 led to inadequate P-TEFb inhibition under serum starvation and impaired myogenic differentiation of C2C12 cells in vitro (36).…”

Section: Introductionmentioning

confidence: 96%

HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

Hong¹,

Chen²,

Huang³

et al. 2012

J. Clin. Invest.

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The native capacity of adult skeletal muscles to regenerate is vital to the recovery from physical injuries and dystrophic diseases. Currently, the development of therapeutic interventions has been hindered by the complex regulatory network underlying the process of muscle regeneration. Using a mouse model of skeletal muscle regeneration after injury, we identified hexamethylene bisacetamide inducible 1 (HEXIM1, also referred to as CLP-1), the inhibitory component of the positive transcription elongation factor b (P-TEFb) complex, as a pivotal regulator of skeletal muscle regeneration. Hexim1-haplodeficient muscles exhibited greater mass and preserved function compared with those of WT muscles after injury, as a result of enhanced expansion of satellite cells. Transplanted Hexim1-haplodeficient satellite cells expanded and improved muscle regeneration more effectively than WT satellite cells. Conversely, HEXIM1 overexpression restrained satellite cell proliferation and impeded muscle regeneration. Mechanistically, dissociation of HEXIM1 from P-TEFb and subsequent activation of P-TEFb are required for satellite cell proliferation and the prevention of early myogenic differentiation. These findings suggest a crucial role for the HEXIM1/P-TEFb pathway in the regulation of satellite cell-mediated muscle regeneration and identify HEXIM1 as a potential therapeutic target for degenerative muscular diseases.

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Section: Introductionmentioning

confidence: 96%

HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

Hong¹,

Chen²,

Huang³

et al. 2012

J. Clin. Invest.

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“…About 50% of P-TEFb is found to associate with HEXIM1 in cells, suggesting the importance of HEXIM1 in the regulation of P-TEFb [25]. Besides P-TEFb, other HEXIM1 binding proteins were identified, including MyoD, histone deacetylases, importin alpha, HDM2, nucleophosmin (NPM), p53, estrogen receptor alpha (ERα), NF-κB, and glucocorticoid receptor (GR) [32–39]. Some of the HEXIM1 binding proteins, such as HDM2 and NPM, regulate P-TEFb activity through the modulation of HEXIM1 proteins [34,35].…”

Section: Introductionmentioning

confidence: 99%

HEXIM1 Induces Differentiation of Human Pluripotent Stem Cells

et al. 2013

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Hexamethylene bisacetamide inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb), which is composed of cyclin-dependent kinase 9 (CDK9)/cyclin T1. P-TEFb is an essential regulator for the transcriptional elongation by RNA polymerase II. A genome-wide study using human embryonic stem cells shows that most mRNA synthesis is regulated at the stage of transcription elongation, suggesting a possible role for P-TEFb/HEXIM1 in the gene regulation of stem cells. In this report, we detected a marked increase in HEXIM1 protein levels in the differentiated human pluripotent stem cells (hPSCs) induced by LY294002 treatment. Since no changes in CDK9 and cyclin T1 were observed in the LY294002-treated cells, increased levels of HEXIM1 might lead to inhibition of P-TEFb activity. However, treatment with a potent P-TEFb inhibiting compound, flavopiridol, failed to induce hPSC differentiation, ruling out the possible requirement for P-TEFb kinase activity in hPSC differentiation. Conversely, differentiation was observed when hPSCs were incubated with hexamethylene bisacetamide, a HEXIM1 inducing reagent. The involvement of HEXIM1 in the regulation of hPSCs was further supported when overexpression of HEXIM1 concomitantly induced hPSC differentiation. Collectively, our study demonstrates a novel role of HEXIM1 in regulating hPSC fate through a P-TEFb-independent pathway.

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“…As well as interaction with the E proteins required for transcriptional activity MyoD has also been reported to interact with a wide range of other proteins including c-jun [112], CTCF [113], BAF60c [114], CLP-1 and HDAC at the cyclin D promoter [115], TAZ at the Mgn promoter [116] and -catenin [117]. MyoD can also interact with cell cycle regulators such as pRB [118] and cdk4 [119] to induce cell cycle withdrawal directly during myogenic differentiation.…”

Section: Biochemical Activity Of the Mrfsmentioning

confidence: 99%

Skeletal Muscle - From Myogenesis to Clinical Relations

Sweetman¹

2012

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CLP-1 associates with MyoD and HDAC to restore skeletal muscle cell regeneration

Cited by 17 publications

References 30 publications

HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

HEXIM1 Induces Differentiation of Human Pluripotent Stem Cells

Skeletal Muscle - From Myogenesis to Clinical Relations

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