mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-ß1-induced collagen biosynthesis.
Sci Signal
; 12(582)2019 05 21.
Article
em En
| MEDLINE
| ID: mdl-31113850
ABSTRACT
The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)-producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue repair is complete, lead to pathological fibrosis and are also features of the stromal response in cancer. Myofibroblast differentiation is accompanied by changes in cellular metabolism, including increased glycolysis, to meet the biosynthetic demands of enhanced ECM production. Here, we showed that transforming growth factor-ß1 (TGF-ß1), the key pro-fibrotic cytokine implicated in multiple fibrotic conditions, increased the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. We further delineated the signaling pathways involved and showed that TGF-ß1-induced ATF4 production depended on cooperation between canonical TGF-ß1 signaling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn, promoted the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Our findings suggest that targeting the TGF-ß1-mTORC1-ATF4 axis may represent a novel therapeutic strategy for interfering with myofibroblast function in fibrosis and potentially in other conditions, including cancer.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Serina
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Colágeno
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Fator 4 Ativador da Transcrição
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Fator de Crescimento Transformador beta1
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Alvo Mecanístico do Complexo 1 de Rapamicina
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Glicina
Limite:
Humans
Idioma:
En
Revista:
Sci Signal
Assunto da revista:
CIENCIA
/
FISIOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido