Dataset Information

Traf7, a MyoD1 transcriptional target, regulates nuclear factor-?B activity during myogenesis.

ABSTRACT: We have identified the E3 ligase Traf7 as a direct MyoD1 target and show that cell cycle exit-an early event in muscle differentiation-is linked to decreased Traf7 expression. Depletion of Traf7 accelerates myogenesis, in part through downregulation of nuclear factor-?B (NF-?B) activity. We used a proteomic screen to identify NEMO, the NF-?B essential modulator, as a Traf7-interacting protein. Finally, we show that ubiquitylation of NF-?B essential modulator is regulated exclusively by Traf7 activity in myoblasts. Our results suggest a new mechanism by which MyoD1 function is coupled to NF-?B activity through Traf7, regulating the balance between cell cycle progression and differentiation during myogenesis.

SUBMITTER: Tsikitis M

PROVIDER: S-EPMC2999857 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other

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Publications

Traf7, a MyoD1 transcriptional target, regulates nuclear factor-κB activity during myogenesis.

Tsikitis Mary M Acosta-Alvear Diego D Blais Alexandre A Campos Eric I EI Lane William S WS Sánchez Irma I Dynlacht Brian D BD

EMBO reports 20101015 12

We have identified the E3 ligase Traf7 as a direct MyoD1 target and show that cell cycle exit-an early event in muscle differentiation-is linked to decreased Traf7 expression. Depletion of Traf7 accelerates myogenesis, in part through downregulation of nuclear factor-κB (NF-κB) activity. We used a proteomic screen to identify NEMO, the NF-κB essential modulator, as a Traf7-interacting protein. Finally, we show that ubiquitylation of NF-κB essential modulator is regulated exclusively by Traf7 act ...[more]

PMID: 20948544

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Project description:HNF-4 (hepatocyte nuclear factor 4) is a key regulator of liver-specific gene expression in mammals. We have shown previously that the activity of the human APOC3 (apolipoprotein C-III) promoter is positively regulated by the anti-inflammatory cytokine TGFbeta (transforming growth factor beta) and its effectors Smad3 (similar to mothers against decapentaplegic 3) and Smad4 proteins via physical and functional interactions between Smads and HNF-4. We now show that the pro-inflammatory cytokine TNFalpha (tumour necrosis factor alpha) antagonizes TGFbeta for the regulation of APOC3 gene expression in hepatocytes. TNFalpha was a strong inhibitor of the activity of apolipoprotein promoters that harbour HNF-4 binding sites and this inhibition required HNF-4. Using specific inhibitors of TNFalpha-induced signalling pathways, it was shown that inhibition of the APOC3 promoter by TNFalpha involved NF-kappaB (nuclear factor kappaB). Latent membrane protein 1 of the Epstein-Barr virus, which is an established potent activator of NF-kappaB as well as wild-type forms of various NF-kappaB signalling mediators, also inhibited strongly the APOC3 promoter and the transactivation function of HNF-4. TNFalpha had no effect on the stability or the nuclear localization of HNF-4 in HepG2 cells, but inhibited the binding of HNF-4 to the proximal APOC3 HRE (hormone response element). Using the yeast-transactivator-GAL4 system, we showed that both AF-1 and AF-2 (activation functions 1 and 2) of HNF-4 are inhibited by TNFalpha and that this inhibition was abolished by overexpression of different HNF-4 co-activators, including PGC-1 (peroxisome-proliferator-activated-receptor-gamma co-activator 1), CBP [CREB (cAMP-response-element-binding protein) binding protein] and SRC3 (steroid receptor co-activator 3). In summary, our findings indicate that TNFalpha, or other factors that trigger an NF-kappaB response in hepatic cells, inhibit the transcriptional activity of the APOC3 and other HNF-4-dependent promoters and that this inhibition could be accounted for by a decrease in DNA binding and the down-regulation of the transactivation potential of the AF-1 and AF-2 domains of HNF-4.

Dataset Information

Traf7, a MyoD1 transcriptional target, regulates nuclear factor-?B activity during myogenesis.

Publications

Traf7, a MyoD1 transcriptional target, regulates nuclear factor-κB activity during myogenesis.

Similar Datasets

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