RESUMEN
In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer.
Asunto(s)
Proteína Adaptadora GRB2/genética , Proteína Oncogénica v-akt/genética , Neoplasias Ováricas/genética , Fosfohidrolasa PTEN/genética , Fosfolipasa C gamma/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Animales , Carcinogénesis/genética , Proliferación Celular/genética , Femenino , Proteína Adaptadora GRB2/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Neoplasias Ováricas/patología , Fosfohidrolasa PTEN/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositoles/metabolismo , Fosfolipasa C gamma/biosíntesis , Pronóstico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/biosíntesis , Transducción de SeñalRESUMEN
Cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and polyubiquitination by SCF(FBX4-alphaB crystallin). Inhibition of cyclin D1 proteolysis has been implicated as a causative factor leading to its overexpression in breast and esophageal carcinomas; however, the contribution of stable cyclin D1 to the genesis of such carcinomas has not been evaluated. We therefore generated transgenic mice wherein expression of either wild-type or a stable cyclin D1 allele (D1T286A) is regulated by MMTV-LTR. MMTV-D1T286A mice developed mammary adenocarcinomas at an increased rate relative to MMTV-D1 mice. Similar to human cancers that overexpress cyclin D1, D1T286A tumors were estrogen receptor-positive and exhibited estrogen-dependent growth. Collectively, these results suggest that temporal control of cyclin D1 subcellular localization and proteolysis is critical for maintenance of homeostasis within the mammary epithelium.
Asunto(s)
Transporte Activo de Núcleo Celular/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Neoplasias Mamarias Animales/etiología , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Experimentales/etiología , Neoplasias Mamarias Experimentales/metabolismo , Adenocarcinoma/etiología , Adenocarcinoma/metabolismo , Adenocarcinoma/virología , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Células Cultivadas , Ciclina D1/fisiología , Femenino , Homeostasis/genética , Humanos , Hidrólisis , Neoplasias Mamarias Animales/virología , Neoplasias Mamarias Experimentales/virología , Virus del Tumor Mamario del Ratón/patogenicidad , Ratones , Ratones Transgénicos , Fosforilación , Fracciones Subcelulares/metabolismo , Ubiquitinación/genéticaRESUMEN
Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by overexpression of cyclin D1 due to the t(11;14) chromosomal translocation. While expression of cyclin D1 correlates with MCL development, expression of wild-type (WT) cyclin D1 transgene in murine lymphocytes is unable to drive B-cell lymphoma. As cyclin D1 mutants that are refractory to nuclear export display heighten oncogenicity in vitro compared with WT D1, we generated mice expressing FLAG-D1/T286A, a constitutively nuclear mutant, under the control of the immunoglobulin enhancer, Emu. D1/T286A transgenic mice universally develop a mature B-cell lymphoma. Expression of D1/T286A in B lymphocytes results in S phase entry in resting lymphocytes and increased apoptosis in spleens of young premalignant mice. Lymphoma onset correlates with perturbations in p53/MDM2/p19Arf expression and with BcL-2 overexpression suggesting that alterations in one or both of these pathways may contribute to lymphoma development. Our results describe a cyclin D1-driven model of B-cell lymphomagenesis and provide evidence that nuclear-retention of cyclin D1 is oncogenic in vivo.