Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex.
Hum Mol Genet
; 26(2): 407-419, 2017 01 15.
Article
em En
| MEDLINE
| ID: mdl-28013293
ABSTRACT
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder featured with multi-organ benign tumours. Disruption of TSC1/TSC2 complex suppression on mammalian/mechanistic target of rapamycin (mTOR) signalling causes TSC. Hyperactive mTOR-mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC-associated tumours. In this study, we demonstrated that osteopontin (OPN) was dramatically reduced by loss of TSC1/TSC2 complex in Tsc2-null mouse embryonic fibroblasts (MEFs), rat uterine leiomyoma-derived Tsc2-deficient cells, genetically modified mouse TSC models, and clinical samples. TSC1/TSC2 complex upregulation of OPN expression is mediated by transcription factor SOX9 in an mTOR-independent manner. Moreover, ablation of OPN by deficient TSC1/TSC2 complex contributed to inactivation of AKT in TSC cells. Lastly, the abundance of OPN dictated the potency of cell proliferation and tumour development. Therefore, loss of TSC1/TSC2 complex led to mTOR-independent inhibition of AKT at least partially through downregulation of the SOX9-OPN signalling cascade. We suggest that the decreased SOX9-OPN-AKT signalling pathway safeguard against the development of malignant tumours in TSC patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esclerose Tuberosa
/
Proteínas Supressoras de Tumor
/
Proteína Oncogênica v-akt
/
Osteopontina
/
Fatores de Transcrição SOX9
/
Serina-Treonina Quinases TOR
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article