RESUMEN
BBS4 is one of several proteins that cause Bardet-Biedl syndrome (BBS), a multisystemic disorder of genetic and clinical complexity. Here we show that BBS4 localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery to recruit PCM1 (pericentriolar material 1 protein) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division and apoptotic cell death. Expression of two truncated forms of BBS4 that are similar to those found in some individuals with BBS had a similar effect on PCM1 and microtubules. Our findings indicate that defective targeting or anchoring of pericentriolar proteins and microtubule disorganization contribute to the BBS phenotype and provide new insights into possible causes of familial obesity, diabetes and retinal degeneration.
Asunto(s)
Síndrome de Bardet-Biedl/metabolismo , Ciclo Celular , Centrosoma/metabolismo , Microtúbulos/metabolismo , Proteínas/metabolismo , Animales , Apoptosis , Autoantígenos , Síndrome de Bardet-Biedl/patología , Células COS , Proteínas de Ciclo Celular/metabolismo , Centrosoma/patología , Chlorocebus aethiops , Dineínas/metabolismo , Silenciador del Gen , Células HeLa , Humanos , Etiquetado Corte-Fin in Situ , Proteínas Asociadas a Microtúbulos , Fragmentos de Péptidos/inmunología , Fenotipo , Unión Proteica , Subunidades de Proteína , Transporte de Proteínas , Proteínas/antagonistas & inhibidores , Proteínas/genética , ARN Interferente Pequeño/farmacología , Conejos , Saccharomyces cerevisiae , Técnicas del Sistema de Dos HíbridosRESUMEN
NDRG1 is a hypoxia-inducible protein, whose modulated expression is associated with the progression of human cancers. Here, we reveal that NDRG1 is markedly upregulated in the cytoplasm and on the membrane in human hepatocellular carcinoma (HCC). We demonstrate further that hypoxic stress increases the cytoplasmic expression of NDRG1 in vitro, but does not result in its localization on the plasma membrane. However, grown within an HCC-xenograft in vivo, cells express NDRG1 in the cytoplasm and on the plasma membrane. In conclusion, hypoxia is a potent inducer of NDRG1 in HCCs, albeit requiring additional stimuli within the tumour microenvironment for its recruitment to the membrane.