Maintenance of the Undifferentiated State in Myogenic Progenitor Cells by TGFß Signaling is Smad Independent and Requires MEK Activation.
Int J Mol Sci
; 21(3)2020 02 05.
Article
en En
| MEDLINE
| ID: mdl-32033454
ABSTRACT
Transforming growth factor ß (TGFß) is a pluripotent cytokine and regulates a myriad of biological processes. It has been established that TGFß potently inhibits skeletal muscle differentiation; however, the molecular mechanism is not clearly defined. Previously, we reported that inhibition of the TGFß canonical pathway by an inhibitory Smad, Smad7, does not reverse this effect on differentiation, suggesting that activation of receptor Smads (R-Smads) by TGFß is not responsible for repression of myogenesis. In addition, pharmacological blockade of Smad3 activation by TGFß did not reverse TGFß's inhibitory effect on myogenesis. In considering other pathways, we observed that TGFß potently activates MEK/ERK, and a pharmacological inhibitor of MEK reversed TGFß's inhibitory effect on myogenesis, as indicated by a myogenin promoter-reporter gene, sarcomeric myosin heavy chain accumulation, and phenotypic myotube formation. Furthermore, we found that c-Jun, a known potent repressor of myogenesis, which is coincidently also a down-stream target of MEK/ERK signaling, was phosphorylated and accumulates in the nucleus in response to TGFß activation. Taken together, these observations support a model in which TGFß activates a MEK/ERK/c-Jun pathway to repress skeletal myogenesis, maintaining the pluripotent undifferentiated state in myogenic progenitors.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células Madre
/
Transducción de Señal
/
Diferenciación Celular
/
Factor de Crecimiento Transformador beta
/
Sistema de Señalización de MAP Quinasas
/
Desarrollo de Músculos
/
Proteínas Smad
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2020
Tipo del documento:
Article