RESUMO
Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Transporte/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Antineoplásicos/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Chaperonas Moleculares/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Nicotine replacement therapy, bupropion, nortriptyline, clonidine, and varenicline are all effective, although insufficient evidence exists to recommend one intervention over another. Effective nonpharmacologic interventions include brief physician advice and more intensive counseling, such as proactive telephone counseling, group and individual counseling, and use of quit lines.