RESUMEN
The tumor-suppressing function of SMAD4 is frequently subverted during mammary tumorigenesis, leading to cancer growth, invasion, and metastasis. A long-standing concept is that SMAD4 is not regulated by phosphorylation but ubiquitination. Our search for signaling pathways regulated by breast tumor kinase (BRK), a nonreceptor protein tyrosine kinase that is up-regulated in ~80% of invasive ductal breast tumors, led us to find that BRK competitively binds and phosphorylates SMAD4 and regulates transforming growth factor-ß/SMAD4 signaling pathway. A constitutively active BRK (BRK-Y447F) phosphorylates SMAD4, resulting in its recognition by the ubiquitin-proteasome system, which accelerates SMAD4 degradation. Activated BRK-mediated degradation of SMAD4 is associated with the repression of tumor suppressor gene FRK and increased expression of mesenchymal markers, SNAIL, and SLUG. Thus, our data suggest that combination therapies targeting activated BRK signaling may have synergized the benefits in the treatment of SMAD4 repressed cancers.
Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteína Smad4/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Proteínas de Neoplasias/genética , Fosforilación , Proteínas Tirosina Quinasas/genética , Proteína Smad4/genética , Factor de Crecimiento Transformador beta/metabolismo , Tirosina/metabolismo , UbiquitinaciónRESUMEN
From December 1977 until April 1978 a hepatitis A outbreak occurred in an institution for the mentally retarded. The institution housed 311 residents and had a staff of 308. The outbreak was studied by enzyme-linked immunosorbent assays for hepatitis A antigen and antibodies, and by liver function tests in serum. When the investigations started, 13 residents and one staff member were ill and already seropositive; 34 of the 182 residents that were seronegative at that time and 12 of the 223 seronegative staff members subsequently developed disease. Out of the 60 cases 32 were asymptomatic; 19 cases with jaundice were seen. Normal human immunoglobulin was administered to a large part of the seronegative group, but the effect is difficult to interpret as the immunoglobulin was often given after the presumed time of infection and failed to protect. Elevated liver enzyme levels were demonstrated in 38 of 60 patients.
