RESUMEN
The transcriptional coactivator AIB1 is an oncogene overexpressed in different types of tumors, including breast cancer. Although the subcellular compartimentalization of AIB1 seems to be intimately linked to abnormal proliferation, the molecular mechanisms that regulate its subcellular distribution are not well defined. Here, we report that the nuclear accumulation and half-life of AIB1 vary between cancer cell lines. Using these differences as an experimental model, our results reveal that alterations to the Akt signaling pathway and nuclear export determine the stability of AIB1 and nuclear content of this coactivator. Moreover, our results show that AIB1 is degraded in the nucleus by the proteasome in an ubiquitin-dependent manner. However, this process does not require phosphorylation by GSK3, thereby revealing an alternative mechanism for regulating the turnover of AIB1. We define a new region at the carboxy terminus of AIB1 that is required for proteasome-dependent transcriptional activation and is preceded by a PEST domain that is required for adequate protein turnover. Based on differences in Akt signaling and the subcellular distribution of AIB1 between different cell lines, our results suggest that dysregulation of nuclear shuttling and proteasomal degradation may modulate the oncogenic potential of AIB1.
Asunto(s)
Glucógeno Sintasa Quinasa 3/metabolismo , Proteína Oncogénica v-akt/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Procesamiento Proteico-Postraduccional , Factores de Transcripción/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular/metabolismo , Células HeLa , Humanos , Leupeptinas/farmacología , Modelos Biológicos , Coactivador 3 de Receptor Nuclear , Proteína Oncogénica v-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Estructura Terciaria de Proteína/fisiología , Transducción de Señal/fisiología , Distribución Tisular , Factores de Transcripción/química , Ubiquitinación/fisiologíaRESUMEN
Here we report a new model of pre-clinical breast cancer which has been generated by overexpressing the steroid receptor coactivator AIB1 at moderate levels in breast epithelium. Transgenic female mice display mammary hyperplasia at the onset of puberty, consistent with enhanced proliferation of primary mammary epithelial cultures and augmented levels of cyclin D1 and E-cadherin. Studies of BrdU incorporation revealed that AIB1 localizes to the nucleus during or after S phase, implicating a new role for AIB1 in cell-cycle progression subsequent to G1. Our findings suggest that moderate overexpression of AIB1 may represent one of the pre-neoplastic changes in breast tissue.
