RESUMEN
Many cellular processes, ranging from cell division to differentiation, are controlled by nuclear pore complexes (NPCs). However, studying the contributions of individual NPC subunits to these processes in vertebrates has long been impeded by their complexity and the lack of efficient genetic tools. Here, we use genome editing in mouse embryonic stem cells (mESCs) to characterize the role of NPC structural components, focusing on the short arm of the Y-complex that comprises Nup85, Seh1 and Nup43. We show that Seh1 and Nup43, although dispensable in pluripotent mESCs, are required for their normal cell growth rates, their viability upon differentiation and for the maintenance of proper NPC density. mESCs with an N-terminally truncated Nup85 mutation (in which interaction with Seh1 is greatly impaired) feature a similar reduction of NPC density. However, their proliferation and differentiation are unaltered, indicating that it is the integrity of the Y-complex, rather than the number of NPCs, that is critical to ensure these processes.
Asunto(s)
Células Madre Embrionarias de Ratones , Poro Nuclear , Animales , Diferenciación Celular/genética , Edición Génica , Ratones , Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/genéticaRESUMEN
AIM: To explore the independent prognostic value of NUP43 in terms of overall survival (OS) and the mechanisms of its dysregulation in breast cancer. PATIENTS & METHODS: Bioinformatic analysis was performed by using data from The Cancer Genome Atlas-breast invasive carcinoma. RESULTS: High NUP43 expression was an independent prognostic factor of poor OS in luminal A subtype (HR: 2.400; 95% CI: 1.070-5.379; p = 0.034) and in HER2+ subtype (HR: 10.578; 95% CI: 1.850-60.473; p = 0.008). NUP43 DNA amplification was associated with elevated NUP43 expression, while DNA deletion was associated with decreased NUP43 transcription. CONCLUSION: NUP43 upregulation was related to DNA amplification and might independently predict poor OS in luminal A and in HER2+ breast tumors.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Proteínas de Complejo Poro Nuclear/metabolismo , Receptor ErbB-2/metabolismo , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/mortalidad , Biología Computacional , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Proteínas de Complejo Poro Nuclear/genética , Análisis de Secuencia de ADNRESUMEN
Nuclear pore complexes (NPC) form nuclear pores that cross the nuclear envelope and allow molecules to transport between the nucleus and the cytoplasm. We solved the crystal structure of human Nup43 (hNUP43), an important component in the Nup107 subcomplex of NPC. hNup43 adopts a seven-bladed ß-propeller fold. We confirmed by ITC that neither human Nup37 (hNup37) nor human Nup133 (hNup133) interacts with hNup43. We demonstrated by analytical gel filtration that the human Nup85-Seh1L binary complex recruits hNup43 to form a ternary complex. Based on amino acid sequence analysis, we predicted the hNup85-hSeh1L binding surface of hNup43.