Regulation of TAZ Expression by Cyclic Stretch
Notice bibliographique
Résumé
It is increasingly recognized that fibrosis‐related phenotype transitions (e.g. EMT and fibrobrolast‐myofibroblast transition) are brought about by the interplay between chemical (e.g. TGFβ) and mechanical (e.g. stretch) stimuli, which, in part, act through cytoskeleton‐regulated transcription factors. Among these, the Hippo effector TAZ and the Rho/actin‐regulated myocardin‐related transcription factor (MRTF) are TGFβ‐ and mechano‐sensitive transcriptional co‐activators, which play key roles in the pathogenesis of organ fibrosis. Previously we have shown a multilevel crosstalk between TAZ and MRTF. Moreover, we found that TGFβ is a strong inducer of TAZ protein and mRNA expression, an effect mediated by p38‐dependent MRTF activation, independent of a net nuclear translocation of MRTF or TAZ. These results revealed that, in addition to TAZ nuclear translocation, the regulation of TAZ expression (a hitherto poorly characterized process) is also a critical feature of fibrogenesis. Since mechanical stimuli are prominent inducers of fibrosis, we sought to determine if cyclic stretch impacts TAZ expression and to investigate the potential role of the RhoGTPase/MRTF signaling pathway in this process. Cyclic stretch (10%, 1 Hz) increased MRTF‐transcriptional activity, measured by a CArG box‐ (cis‐element for MRTF) containing luciferase reporter construct, between 3 and 6 hr in C3H10T1/2 cells. Overexpression of Rho family small GTPases (RhoA, Rac1 and Cdc42) known to be activated by stretch and to induce MRTF translocation, were sufficient to enhance the activity of a TAZ promoter luciferase reporter (TAZ‐Luc). Consistently, cyclic stretch increased TAZ protein and mRNA expression, and activated TAZ‐Luc. TAZ‐Luc activation was abolished by MRTF inhibition or the mutation of the CArG box within the reporter (mtTAZ‐Luc). The stretch‐induced activation of TAZ expression was a universal phenomenon, since similar effects were observed in Interstitial Rat Mesenchyme Cells (IRMC) and Human Pulmonary Microvascular Endothelial Cells (HPMEC) as well. Finally, since the redox‐regulator pirin was recently suggested to be an upstream regulator of MRTF, we checked its potential involvement in the regulation of TAZ expression. While CCT‐251236, a pirin‐binding compound abolished the TGFβ‐induced TAZ expression, pirin silencing failed to recapitulate this effect. This suggests that the drug has alternative targets and MRTF can be activated in a pirin‐independent manner. Taken together, our studies show that critical chemical and mechanical fibrogenic stimuli increase TAZ expression and MRTF is a key mediator of this effect, both via classic (Rho‐mediated, translocation‐dependent) and by “non‐canonical” (phosphorylation‐induced activation) mechanisms. We propose that the ensuing rise in TAZ expression potently accelerates and exacerbates fibrogenic phenotype transitions. Support or Funding Information Kidney Foundation of Canada and Natural Sciences and Engineering Research Council of Canada (AK)
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».