RESUMEN
Birt-Hogg-Dubé syndrome (BHD) is a human cancer disorder caused by mutations in the tumor suppressor gene Folliculin (FLCN) with unknown biological functions. Here, we show that the Drosophila homolog of FLCN, dFLCN (a.k.a. dBHD) localizes to the nucleolus and physically interacts with the 19S proteasomal ATPase, Rpt4, a nucleolar resident and known regulator of rRNA transcription. Downregulation of dFLCN resulted in an increase in nucleolar volume and upregulation of rRNA synthesis, whereas dFLCN overexpression reduced rRNA transcription and counteracted the effects of Rpt4 on rRNA production by preventing the association of Rpt4 with the rDNA locus. We further show that human FLCN exhibited evolutionarily conserved function and that Rpt4 knockdown inhibits the growth of FLCN-deficient human renal cancer cells in mouse xenografts. Our study suggests that FLCN functions as a tumor suppressor by negatively regulating rRNA synthesis.
Asunto(s)
Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Birt-Hogg-Dubé/metabolismo , Proteínas de Drosophila/metabolismo , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/fisiología , ARN Ribosómico/genética , Proteínas Supresoras de Tumor/fisiología , Adenosina Trifosfatasas/metabolismo , Animales , Animales Modificados Genéticamente , Proteínas Portadoras/metabolismo , Línea Celular , Núcleo Celular/metabolismo , ADN Ribosómico/metabolismo , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Ratones Desnudos , Unión Proteica , Transporte de Proteínas , Proteínas Proto-Oncogénicas/genética , Precursores del ARN/metabolismo , ARN Ribosómico/biosíntesis , Trasplante Heterólogo , Carga Tumoral/genética , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
Organismal aging is influenced by a multitude of intrinsic and extrinsic factors, and heterochromatin loss has been proposed to be one of the causes of aging. However, the role of heterochromatin in animal aging has been controversial. Here we show that heterochromatin formation prolongs lifespan and controls ribosomal RNA synthesis in Drosophila. Animals with decreased heterochromatin levels exhibit a dramatic shortening of lifespan, whereas increasing heterochromatin prolongs lifespan. The changes in lifespan are associated with changes in muscle integrity. Furthermore, we show that heterochromatin levels decrease with normal aging and that heterochromatin formation is essential for silencing rRNA transcription. Loss of epigenetic silencing and loss of stability of the rDNA locus have previously been implicated in aging of yeast. Taken together, these results suggest that epigenetic preservation of genome stability, especially at the rDNA locus, and repression of unnecessary rRNA synthesis, might be an evolutionarily conserved mechanism for prolonging lifespan.
