Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective TORC2 Activation.
J Biol Chem
; 287(3): 2090-8, 2012 Jan 13.
Article
em En
| MEDLINE
| ID: mdl-22139837
ABSTRACT
Androgen receptor (AR) plays a central role in prostate cancer (PCa) growth, with androgen deprivation or AR down-regulation causing cell-cycle arrest and accumulation of the p27 cyclin-dependent kinase inhibitor. The molecular basis for this AR regulation of cell-cycle progression remains unclear. Here we demonstrate that androgen can rapidly reduce p27 protein in PCa cells by increasing its proteasome-mediated degradation. This rapid androgen-stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157. Significantly, androgen increased TORC2-mediated AKT S473 phosphorylation without affecting the PDK1-mediated AKT T308 phosphorylation or TORC1 activity. The TORC2 activation was further supported by enhanced mTOR/RICTOR association and increased phosphorylation of additional TORC2 substrates, SGK1 and PKCα. The androgen-stimulated nuclear translocation of AR was associated with markedly-increased nuclear SIN1, a critical component of TORC2. Finally, the androgen-mediated TORC2/AKT activation targets a subset of AKT substrates including p27 and FOXO1, but not PRAS40. This study reveals a pathway linking AR to a selective activation of TORC2, the subsequent activation of AKT, and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival. These findings establish that TORC2 can function as a central regulator of growth in response to signals that are distinct from those regulating TORC1, and support efforts to target TORC2 for cancer therapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Receptores Androgênicos
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Transativadores
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Proliferação de Células
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Inibidor de Quinase Dependente de Ciclina p27
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Proteólise
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article