RESUMEN
Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.
Asunto(s)
Subunidad Apc7 del Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Encéfalo/enzimología , Heterocromatina/metabolismo , Discapacidad Intelectual/enzimología , Células-Madre Neurales/enzimología , Neurogénesis , Adolescente , Animales , Antígenos CD , Subunidad Apc7 del Ciclosoma-Complejo Promotor de la Anafase/genética , Conducta Animal , Encéfalo/crecimiento & desarrollo , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular , Niño , Preescolar , Modelos Animales de Enfermedad , Femenino , Heterocromatina/genética , Humanos , Lactante , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Discapacidad Intelectual/psicología , Inteligencia , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitosis , Mutación , Células-Madre Neurales/patología , Proteolisis , Transducción de Señal , Síndrome , Ubiquitinación , Adulto JovenRESUMEN
PURPOSE: Anaphase promoting complex (APC/C) is an E3 ligase enzyme, which ubiquinates various proteins involved in the cell cycle. This protein complex may have a pivotal role in the cell cycle control affecting pathological conditions such as cancer. APC7 and APC2 subunits of the APC/C complex are involved in the substrate recognition and the catalytic reaction, respectively. MATERIALS AND METHODS: In this study, quantitative Real-time PCR was used to analyse APC2 and APC7 expression in different cancer cell lines as well as AML patient's blood cells. RESULTS: The results showed that APC2 and APC7 subunits were both over expressed in cancer cell lines (p=0.008). The mean expression ratio of APC2 and APC7 in different cancer cells were 2.60±0.22 and 4.83±0.11, respectively. An increase in expression of APC2 and APC7 was seen among 12 out of 14 AML patients (85%). There was a significant positive correlation between APC2 upregulation and the detection of splenomegaly in the patients (r=0.808, p=0.001). CONCLUSION: This was the first study suggesting that APC/C upregulation may contribute to the pathogenesis of cancer and can be used as a molecular biomarker to predict the progression and the prognosis of AML.
