The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis

Nascimento, Elisabete; Cox, Claire; MacArthur, Stewart; Hussain, Shobbir; Trotter, Matthew; Blanco, Sandra; Menon, Suraj; Nichols, Jennifer; Kübler, Bernd; Benitah, Salvador Aznar; Hendrich, Brian; Odom, Duncan T.; Frye, Michaela

doi:10.1038/ncb2385

Cited by 60 publications

(57 citation statements)

References 59 publications

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“…HEK293T cells were transfected with expression vec- tors for Myc, Sin3b, and the acetyltransferase Kat2a (GCN5), and 24 h after transfection the levels of acetylated Myc were assessed by immunoblot with anti-acetyl-Lys in the immunoprecipitates obtained with anti-Myc. The results showed that Kat2a expression resulted in Myc acetylation, as reported previously (53), and that levels of acetylated Myc dramatically decreased upon the expression of Sin3b (Fig. 9A).…”

Section: Sin3b Identified As a Myc Interactor In A Yeast Two-hybridsupporting

confidence: 69%

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Sin3b Interacts with Myc and Decreases Myc Levels

García-Sanz

Quintanilla

Lafita

et al. 2014

Journal of Biological Chemistry

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Background: Myc is an oncogenic transcription factor that is frequently deregulated in cancer, and Sin3b is a transcriptional regulator that recruits histone deacetylases. Results: A new interaction between the protein Sin3b and Myc that leads to Myc down-regulation is described. Conclusion: Sin3b-Myc interaction regulates Myc levels and activity. Significance: Sin3b adds a second level of control of Myc by directly regulating Myc levels.

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Section: Sin3b Identified As a Myc Interactor In A Yeast Two-hybridsupporting

confidence: 69%

“…Myc has been shown to be acetylated, which regulates Myc stability (49 -52). On the other hand, it has been reported that Sin3a induces deacetylation of Myc protein resulting in decreased Myc stability (53). We asked whether this was also the case with Sin3b.…”

Section: Sin3b Identified As a Myc Interactor In A Yeast Two-hybridmentioning

confidence: 96%

Sin3b Interacts with Myc and Decreases Myc Levels

García-Sanz

Quintanilla

Lafita

et al. 2014

Journal of Biological Chemistry

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“…OVOL1 was specifically observed in the nuclei of cortex and outer root sheath cells, and OVOL2 was present in the nuclei of outer root sheath cells. It is known that OVOL1 is recruited to epidermal differentiation complex genes, leading to promoting keratinocyte differentiation, 11 and OVOL2 suppresses terminal differentiation of keratinocytes by directly repressing c-myc and Notch-1. The nuclear staining of OVOL1 and OVOL2 in ORS and germ (in addition to above mentioned facts) suggests that OVOL1 and OVOL2 are important transcriptional factors …”

Section: Discussionmentioning

confidence: 99%

Activation of the OVOL1-OVOL2 Axis in the Hair Bulb and in Pilomatricoma

Ito

Tsuji

Ohno

et al. 2016

The American Journal of Pathology

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OVOL1 and OVOL2, ubiquitously conserved genes encoding C2H2 zinc finger transcription factors in mammals, control epithelial cell proliferation, and differentiation, including those in skin. OVOL1 and OVOL2 expression is coordinately mediated via the Wnt signaling pathway, and OVOL1 negatively regulates OVOL2 expression in a transcriptional manner. Our previous study of OVOL1 expression in human skin revealed that OVOL1 is preferentially expressed in the inner root sheath of the hair follicle. Therefore, we hypothesized that the OVOL1-OVOL2 axis is involved in normal and neoplastic follicular differentiation. Immunohistochemical analysis showed that OVOL1 and OVOL2 were strongly expressed in a mutually exclusive manner in the cytoplasm of inner root sheath cells and matrix cells, respectively, in normal follicles. OVOL2 was also expressed in pilomatricoma, with only partial expression of OVOL1. Cultured human keratinocytes expressed OVOL1 and OVOL2 on both the mRNA and protein levels. The expression of OVOL2 was higher in keratinocytes transfected with siRNA of OVOL1. Ketoconazole, a hair growth stimulant, up-regulated the expression of OVOL1 but did not affect OVOL2 expression. These results indicated that the OVOL1-OVOL2 axis may actively contribute to cell differentiation and proliferation in the hair bulb, suggesting that the OVOL1 and OVOL2 may be therapeutic targets of hair disorders, including alopecia, and play important roles in the tumorigenesis of pilomatricoma.

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“…Since SIN3A-mediated deacetylation of MYC has been demonstrated to trigger the degradation of this transcription factor (Nascimento et al 2011), it is likely that the dissociation of HDAC-containing complexes upon H3S28 phosphorylation constitutes a convenient mechanism to modulate transcription by inducing local changes in acetylation of chromatin-bound factors, thereby regulating their activity. Given that MSK1/2 were shown to phosphorylate other factors besides histone H3 (Wiggin et al 2002), we cannot exclude the possibility that such modifications, in addition to H3S28ph, play a role in transcriptional induction of stress-induced genes.…”

Section: Discussionmentioning

confidence: 99%

H3S28 phosphorylation is a hallmark of the transcriptional response to cellular stress

et al. 2014

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The selectivity of transcriptional responses to extracellular cues is reflected by the deposition of stimulus-specific chromatin marks. Although histone H3 phosphorylation is a target of numerous signaling pathways, its role in transcriptional regulation remains poorly understood. Here, for the first time, we report a genome-wide analysis of H3S28 phosphorylation in a mammalian system in the context of stress signaling. We found that this mark targets as many as 50% of all stress-induced genes, underlining its importance in signal-induced transcription. By combining ChIP-seq, RNA-seq, and mass spectrometry we identified the factors involved in the biological interpretation of this histone modification. We found that MSK1/ 2-mediated phosphorylation of H3S28 at stress-responsive promoters contributes to the dissociation of HDAC corepressor complexes and thereby to enhanced local histone acetylation and subsequent transcriptional activation of stress-induced genes. Our data reveal a novel function of the H3S28ph mark in the activation of mammalian genes in response to MAP kinase pathway activation.

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The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis

Cited by 60 publications

References 59 publications

Sin3b Interacts with Myc and Decreases Myc Levels

Sin3b Interacts with Myc and Decreases Myc Levels

Activation of the OVOL1-OVOL2 Axis in the Hair Bulb and in Pilomatricoma

H3S28 phosphorylation is a hallmark of the transcriptional response to cellular stress

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