RESUMEN
Autophagy is a lysosome-dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy-mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral-Facial-Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self-regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagosomas/fisiología , Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Autofagia , Proteínas Asociadas a Microtúbulos/metabolismo , Enfermedades Renales Poliquísticas/patología , Proteínas/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Familia de las Proteínas 8 Relacionadas con la Autofagia/genética , Humanos , Lisosomas/metabolismo , Lisosomas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/genética , Enfermedades Renales Poliquísticas/etiología , Enfermedades Renales Poliquísticas/metabolismo , Proteínas/genéticaRESUMEN
OBJECTIVES: Breast cancer represents the second leading cause of cancer mortality among American women and accounts for more than 40â 000 deaths annually. High-mobility group A1 (HMGA1) expression has been implicated in the pathogenesis and progression of human malignant tumours, including breast carcinomas. The aim of this study was to evaluate HMGA1 detection as an indicator for the diagnosis and prognosis of human breast carcinoma. METHODS: HMGA1 expression has been analysed by immunohistochemistry in a large series of breast carcinoma resections (1338) combined on a tissue microarray mainly including the ductal carcinoma variant. The results were then correlated with clinicopathological parameters of patients. RESULTS: HMGA1 overexpression was found in the large majority of breast carcinoma samples and its overexpression positively correlated with HER-2/neu amplification and progesterone receptor, while a negative correlation was found with oestrogen receptor. Conversely, no HMGA1 expression was found in normal breast tissues. CONCLUSIONS: The data reported here indicate that HMGA1 is overexpressed in human breast carcinomas and its levels are associated with a particular endocrine status.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/química , Carcinoma Ductal de Mama/química , Proteínas HMGA/análisis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Clasificación del Tumor , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Receptor ErbB-2/genética , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Análisis de Matrices Tisulares , Regulación hacia ArribaRESUMEN
Several recent studies have reported the Polycomb Repressive Complex 1 member CBX7 as a tumor-suppressor gene whose expression progressively decreases in different human carcinomas in relation with tumor grade, malignant stage and poor prognosis. We have previously demonstrated that CBX7 is able to inhibit the expression of the SPP1 gene, encoding the chemokine osteopontin that is over-expressed in cancer and has a critical role in cancer progression. Here, we have analyzed the mechanism by which CBX7 regulates the SPP1 gene expression. We show that the SPP1 transcriptional regulation mechanism involves the CBX7-interacting protein HMGA1b, that acts as a positive regulator of the SPP1 gene. In fact, we demonstrate that, in contrast with the transcriptional activity of CBX7, HMGA1b is able to increase the SPP1 expression by inducing the activity of its promoter. Moreover, we show that CBX7 interferes with HMGA1b on the SPP1 promoter and counteracts the positive transcriptional activity of HMGA1b on the SPP1 expression. Furthermore, since we found that also the NF-κB complex resulted involved in the modulation of the SPP1 expression in thyroid cells, we suppose that CBX7/HMGA1b/NF-κB could take part in the same transcriptional mechanism that finally leads to the regulation of the SPP1 gene expression. Taken together, our data show the important role played by CBX7 in the negative regulation of the SPP1 gene expression, thus contributing to prevent the acquisition of a malignant phenotype.
