RESUMEN
Inactivation of the tumor suppressor von Hippel-Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.
Asunto(s)
Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteína Reguladora Asociada a mTOR/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/fisiología , Animales , Caenorhabditis elegans , Carcinoma de Células Renales/patología , Procesos de Crecimiento Celular/genética , Proliferación Celular/genética , Células HEK293 , Humanos , Neoplasias Renales/patología , Ubiquitinación/genéticaRESUMEN
SKN-1/Nrf transcription factors regulate diverse biological processes essentially stress defense, detoxification, and longevity. Studies in model organisms have identified a broad range of regulatory processes and mechanisms that profoundly influence SKN-1/Nrf functions. Defining the mechanisms how SKN-1 is regulated will provide insight how cells defend against diverse stressors contributing to aging and disease. In this study, we demonstrate a crucial role for the acetyltransferase CBP-1, the C. elegans homolog of mammalian CREB-binding protein CBP/p300 in the activation of SKN-1. cbp-1 is essential for tolerance of oxidative stress and normal lifespan. CBP-1 directly interacts with SKN-1 and increases SKN-1 protein abundance. In particular CBP-1 modulates SKN-1 nuclear translocation under basal conditions and in response to stress and promotes SKN-1-dependent transcription of protective genes. Moreover, CBP-1 is required for SKN-1 nuclear recruitment, transcriptional activity, and longevity due to reduced insulin/IGF-1-like signaling, mTOR-, and GSK-3 signaling. Our findings establish the acetyltransferase CBP-1 as a critical activator of SKN-1 that directly modulates SKN-1 protein stability, nuclear localization, and function to ascertain normal stress response and lifespan.
