HES6 acts as a transcriptional repressor in myoblasts and can induce the myogenic differentiation program

Gao, Xiangming; Chandra, Tanya; Gratton, Michel-Olivier; Quélo, Isabelle; Prud’homme, Josée; Stifani, Stefano; St‐Arnaud, René

doi:10.1083/jcb.200104058

Cited by 62 publications

(46 citation statements)

References 55 publications

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“…Asynchronously growing 293A cells were transfected with a reporter vector carrying the luciferase gene under the control of the basally active thymidine kinase promoter linked to five tandem copies of the GAL4 upstream activation sequence. As described previously (10,14,17), cotransfection of this reporter plasmid with GAL4bd alone led to an ϳ2-fold activation of transcription above basal level (Fig. 9D, column 2).…”

Section: Fig 4 Phosphorylation Of the Ccn And Sp Domains Of Gro/ Tlsupporting

confidence: 75%

“…In particular, Drosophila Gro is required for sex determination, segmentation, and neural development (1). Vertebrate Gro/TLE proteins contribute to the regulation of neuronal development (2), patterning of the neural tube (3,4), skeletogenesis (5,6), hematopoiesis (7)(8)(9), and myogenesis (10,11). Gro/TLE proteins have no intrinsic DNA binding activity but can be targeted to specific gene regulatory regions due to their ability to interact with a number of different DNA-binding transcription factors.…”

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confidence: 99%

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A Role for Cell Cycle-regulated Phosphorylation in Groucho-mediated Transcriptional Repression

Nuthall¹,

Joachim

Palaparti

et al. 2002

Journal of Biological Chemistry

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Transcriptional corepressors of the Groucho/transducin-like Enhancer of split (Gro/TLE) family are involved in a variety of cell differentiation mechanisms in both invertebrates and vertebrates. They become recruited to specific promoter regions by forming complexes with a number of different DNA-binding proteins thereby contributing to the regulation of multiple genes. To understand how the functions of Gro/TLE proteins are regulated, it was asked whether their ability to mediate transcriptional repression might be controlled by cell cycle-dependent phosphorylation events. It is shown here that activation of p34 cdc2 kinase (cdc2) with okadaic acid is correlated with hyperphosphorylation of Gro/TLEs. Moreover, pharmacological inhibition of cdc2 activity results in Gro/TLE dephosphorylation. In agreement with these findings, a purified cdc2-cyclin B complex can directly phosphorylate Gro/TLEs in vitro. Two separate Gro/TLE domains, the CcN and SP regions, contain sequences that are phosphorylated by cdc2. Deletion of these sequences is correlated with loss of Gro/ TLE phosphorylation by cdc2 in vitro and okadaic acidinduced Gro/TLE hyperphosphorylation in vivo. In addition, Gro/TLEs are phosphorylated during the G 2 /M phase of the cell cycle, and this is correlated with a decreased nuclear interaction. Finally, the transcription repression ability of Gro/TLEs is enhanced by pharmacological inhibition of cdc2. Taken together, these results demonstrate that Gro/TLE proteins are phosphorylated as a function of the cell cycle and implicate phosphorylation events occurring during mitosis in the negative regulation of Gro/TLE activity.In both invertebrates and vertebrates, transcriptional corepressor proteins of the Groucho/transducin-like Enhancer of split (Gro/TLE) 1 family play crucial roles in the regulation of a variety of cell differentiation mechanisms. In particular, Drosophila Gro is required for sex determination, segmentation, and neural development (1). Vertebrate Gro/TLE proteins contribute to the regulation of neuronal development (2), patterning of the neural tube (3, 4), skeletogenesis (5, 6), hematopoiesis (7-9), and myogenesis (10, 11). Gro/TLE proteins have no intrinsic DNA binding activity but can be targeted to specific gene regulatory regions due to their ability to interact with a number of different DNA-binding transcription factors. Examples of these include basic helixloop-helix proteins of the Hes family (12-17), Runt homology domain proteins of the Runt/RUNX family (7,18,19), homeodomain factors containing engrailed homology region 1 motifs (3, 20 -24), winged-helix domain transcription factors (23, 25), and high mobility group box proteins (7, 9). By virtue of these multiple interactions, the general transcription repression activity of Gro/TLE proteins can be recruited in context-dependent manners to specific target genes.Transcriptional repression by Gro/TLE family members is thought to be mediated by at least two mechanisms. Oligomeric Gro/TLEs can interact with both histones (26, 27) ...

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Section: Fig 4 Phosphorylation Of the Ccn And Sp Domains Of Gro/ Tlsupporting

confidence: 75%

mentioning

confidence: 99%

A Role for Cell Cycle-regulated Phosphorylation in Groucho-mediated Transcriptional Repression

Nuthall¹,

Joachim

Palaparti

et al. 2002

Journal of Biological Chemistry

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“…⌬WRPW (Gratton et al, 2003), and pcTOPO-Hes6-VP16 (Gao et al, 2001) were described. A PCR-based strategy was used to generate the mutated constructs pCMV2-HA-Hes6 BAD [primers basic arm defective (BAD)-F, 5Ј-GTGGAGGAGAAGGAACGCGCACGGATCAA-3Ј, and BAD-R, 5Ј-GATCCGTGCGCGTTCCTTCTCCTCCAC-3Ј] and pCMV2-HA-Hes6 LMD [primers LNHLL-motif-defective (LMD)-F, 5Ј-CT-GAACTCGCGAACCACGCGCTAGAATCC-3Ј and LMD-R, 5Ј-GGAT-TCTAGCGCGTGGTTCGCGAGTTCAG-3Ј].…”

Section: Dna Plasmids Plasmids Pcmv2-hemagglutinin (Ha)-hes6mentioning

confidence: 99%

Hes6 Inhibits Astrocyte Differentiation and Promotes Neurogenesis through Different Mechanisms

Jhas¹,

Ciura²,

Bélanger-Jasmin³

et al. 2006

J. Neurosci.

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The mechanisms regulating the generation of cell diversity in the mammalian cerebral cortex are beginning to be elucidated. In that regard, Hairy/Enhancer of split (Hes) 1 and 5 are basic helix-loop-helix (bHLH) factors that inhibit the differentiation of pluripotent cortical progenitors into neurons. In contrast, a related Hes family member termed Hes6 promotes neurogenesis. It is shown here that knockdown of endogenous Hes6 causes supernumerary cortical progenitors to differentiate into cells that exhibit an astrocytic morphology and express the astrocyte marker protein GFAP. Conversely, exogenous Hes6 expression in cortical progenitors inhibits astrocyte differentiation. The negative effect of Hes6 on astrocyte differentiation is independent of its ability to promote neuronal differentiation. We also show that neither its proneuronal nor its anti-gliogenic functions appear to depend on Hes6 ability to bind to DNA via the basic arm of its bHLH domain. Both of these activities require Hes6 to be localized to nuclei, but only its anti-gliogenic function depends on two short peptides, LNHLL and WRPW, that are conserved in all Hes6 proteins. These findings suggest that Hes6 is an important regulator of the neurogenic phase of cortical development by promoting the neuronal fate while suppressing astrocyte differentiation. They suggest further that separate molecular mechanisms underlie the proneuronal and anti-gliogenic activities of Hes6 in cortical progenitor cells.

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“…6), it is capable of promoting expression of neuronal genes in vitro, as well as expanding the myotome in Xenopus embryos (Bae et al, 2000;Koyabi-Nakagawa et al, 2000;Gao et al, 2001;Cossins et al, 2002;Gratton et al, 2003). It was further demonstrated that Hes6 antagonizes and releases the transcriptional repression of Hes1 in both the neuronal and muscle lineages to promote the expression of positively acting bHLH genes, or to promote the action of positively acting bHLH factors (Bae et al, 2000;Koyabi-Nakagawa et al, 2000;Gao et al, 2001;Cossins et al, 2002;Gratton et al, 2003). Of interest, Hes1 is expressed in the cochlear epithelium adjacent to the organ of Corti Zine et al, 2001), and the number of hair cells is increased in Hes1 knockout animals Zine et al, 2001).…”

Section: Hes6 Is Not Sufficient For Hair Cell Differentiation In Cochmentioning

confidence: 99%

“…In contrast to other known Hes genes, however, Hes6 has been shown to be expressed in both precursor and differentiated neuronal cells (Bae et al, 2000;Koyabi-Nakagawa et al, 2000;Pissarra et al, 2000;Vasiliauskas and Stern, 2000;Gratton et al, 2003;Fior and Henrique, 2005). Functional studies further demonstrated that Hes6 promotes neuronal and myogenic differentiation in vitro by antagonizing the action of Hes1 (Bae et al, 2000;Koyabi-Nakagawa et al, 2000;Gao et al, 2001;Cossins et al, 2002;Gratton et al, 2003;Fior and Henrique, 2005). Here, we isolated Hes6 from the cochlear tissue by both differential gene expression and candidate gene approaches.…”

Section: Introductionmentioning

confidence: 99%

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

et al. 2006

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The basic helix-loop-helix (bHLH) gene Hes6 is known to promote neural differentiation in vitro. Here, we report the expression and functional studies of Hes6 in the inner ear. The expression of Hes6 appears to be parallel to that of Math1 (also known as Atoh1), a bHLH gene necessary and sufficient for hair cell differentiation. Hes6 is expressed initially in the presumptive hair cell precursors in the cochlea. Subsequently, the expression of Hes6 is restricted to morphologically differentiated hair cells. Similarly, the expression of Hes6 in the vestibule is in the hair cell lineage. Hes6 is dispensable for hair cell differentiation, and its expression in inner ear hair cells is abolished in the Math1-null animals. Furthermore, the introduction of Hes6 into the cochlea in vitro is not sufficient to promote sensory or neuronal differentiation. Therefore, Hes6 is downstream of Math1 and its expression in the inner ear delineates the sensory lineage. However, the role of Hes6 in the inner ear remains elusive.

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HES6 acts as a transcriptional repressor in myoblasts and can induce the myogenic differentiation program

Cited by 62 publications

References 55 publications

A Role for Cell Cycle-regulated Phosphorylation in Groucho-mediated Transcriptional Repression

A Role for Cell Cycle-regulated Phosphorylation in Groucho-mediated Transcriptional Repression

Hes6 Inhibits Astrocyte Differentiation and Promotes Neurogenesis through Different Mechanisms

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

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