RESUMO
The 40S ribosomal S6 kinase 1 (S6K1) is an important regulator of cell growth. Expression of S6K1 is often elevated in breast cancer cells. However, the transcriptional mechanism of S6K1 overexpression is not understood. In this report, we demonstrate that estrogen activates expression of S6K1 via estrogen receptor (ER)α in ER-positive breast cancer cells. We also show that estrogen acts on the proximal promoter of the S6K1 gene in a mechanism involving the transcriptional factor GATA-3. Finally, we provide data that support the importance of estrogenic regulation of S6K1 expression in breast cancer cell proliferation. S6K1 directly phosphorylates and regulates ligand-independent activity of ERα, while ERα upregulates S6K1 expression. This S6K1-ERα relationship creates a positive feed-forward loop in control of breast cancer cell proliferation. Furthermore, the co-dependent association between S6K1 and ERα may be exploited in the development of targeted breast cancer therapies.
Assuntos
Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Retroalimentação Fisiológica , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Humanos , Células MCF-7 , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos , Fosforilação , Regiões Promotoras Genéticas , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologiaRESUMO
Urological procedures pose specific medical and surgical problems in the patient with a hemorrhagic disorder. Three men, each with a different inherited deficiency involving the factor VIII molecule, underwent prostatectomy. Prolonged postoperative genitourinary hemorrhage was encountered and treated with replacement therapy and the use of inhibitors of fibrinolysis. Successful management of these patients with inherited coagulopathies depends on a thorough understanding of the hemostatic defect, adequate laboratory support and sufficient supplies of blood products.