The protein kinase p38α destabilizes p63 to limit epidermal stem cell frequency and tumorigenic potential.
Sci Signal
; 11(551)2018 10 09.
Article
em En
| MEDLINE
| ID: mdl-30301786
ABSTRACT
The molecular circuitry directing tissue development and homeostasis is hardwired by genetic programs but may also be subject to fine-tuning or major modification by environmental conditions. It remains unclear whether such malleability is at work-particularly in tissues directly in contact with the environment-and contributes to their optimal maintenance and resilience. The protein kinase p38α is activated by physiological cues that signal tissue damage and neoplastic transformation. Here, we found that p38α phosphorylated and thereby destabilized p63, a transcription factor essential for epidermal development. Through this regulatory mechanism, p38α limited the frequency of keratinocytes with stem cell properties and tumorigenic potential. Correspondingly, epidermal loss of p38α expression or activity promoted or correlated with carcinogenesis in mouse and human skin, respectively. Genetic mouse models revealed a tumorigenic mechanism from p38α loss through p63-mediated suppression of the matrix metalloprotease MMP13. These findings illustrate a previously uncharacterized epidermal tumor-suppressive mechanism in which stress-activated signaling induces the contraction of stem cell-like keratinocyte pools.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
/
Células-Tronco
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Fatores de Transcrição
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Queratinócitos
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Proteínas Supressoras de Tumor
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Proteína Quinase 14 Ativada por Mitógeno
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Carcinogênese
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Signal
Ano de publicação:
2018
Tipo de documento:
Article