HERC ubiquitin ligases in cancer

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3-HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies

HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway altering the cellular response to oxidative stress

HERC2 gene encodes an E3 ubiquitin ligase involved in several cellular processes by regulating the ubiquitylation of different protein substrates. Biallelic pathogenic sequence variants in the HERC2 gene are associated with HERC2 Angelman-like syndrome. In pathogenic HERC2 variants, complete absence or marked reduction in HERC2 protein levels are observed. The most common pathological variant, c.1781C > T (p.Pro594Leu), encodes an unstable HERC2 protein. A better understanding of how pathologic HERC2 variants affect intracellular signalling may aid definition of potential new therapies for these disorders. For this purpose, we studied patient-derived cells with the HERC2 Pro594Leu variant. We observed alteration of mitogen-activated protein kinase signalling pathways, reflected by increased levels of C-RAF protein and p38 phosphorylation. HERC2 knockdown experiments reproduced the same effects in other human and mouse cells. Moreover, we demonstrated that HERC2 and RAF proteins form molecular complexes, pull-down and proteomic experiments showed that HERC2 regulates C-RAF ubiquitylation and we found out that the p38 activation due to HERC2 depletion occurs in a RAF/MKK3-dependent manner. The displayed cellular response was that patient-derived and other human cells with HERC2 deficiency showed higher resistance to oxidative stress with an increase in the master regulator of the antioxidant response NRF2 and its target genes. This resistance was independent of p53 and abolished by RAF or p38 inhibitors. Altogether, these findings identify the activation of C-RAF/MKK3/p38 signalling pathway in HERC2 Angelman-like syndrome and highlight the inhibition of RAF activity as a potential therapeutic option for individuals affected with these rare diseases

Il precedente nella giurisprudenza della Corte costituzionale

In una realtà nella quale va affermandosi il principio di eguaglianza formale nell’applicazione della legge e in una situazione in cui la Corte costituzionale viene ad assumere sempre di più il ruolo di garante dei principi costituzionali intangibili dalla maggioranza di governo, acquista rilevanza crescente lo studio del precedente giurisprudenziale della Corte costituzionale, ossia l’anglosassone doctrine of judicial precedent della quale la Corte fa uso ampio e ricorrente, pure se con tecniche ed efficacia differenti. La ricerca si propone di analizzare quanto, nella sostanza e nella forma, l’uso di questi strumenti prelevati dalla Corte nella memoria della propria giurisprudenza, si avvicini a quello dello stare decisis, con le garanzie di certezza e di prevedibilità del diritto che esso comporta

Nota dei curatori

Il prodotto costituisce la prefazione dei curatori al volume "De Bulla Aurea. Andreae II Regis Hungarie. MCCXXII"

Acute aerobic swimming exercise increases nucleotidase activities in rat blood serum

Made available in DSpace on 2015-05-04T16:34:33Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) mr_sengeretal_IOC_2014.pdf: 925467 bytes, checksum: 50965fe4c3ee23940b378aa18d7f6cb6 (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ, Brasil.Pontifícia Universidade Católica do Rio Grande do Sul. Faculdade de Biociências. Departamento de Biologia Celular e Molecular. Laboratório de Neuroquímica e Psicofarmacologia. Porto Alegre, RS, Brasil.Pontifícia Universidade Católica do Rio Grande do Sul.Escola de Educação Física. Porto Alegre, RS, Brasil.Pontifícia Universidade Católica do Rio Grande do Sul. Faculdade de Biociências. Departamento de Biologia Celular e Molecular. Laboratório de Neuroquímica e Psicofarmacologia. Porto Alegre, RS, Brasil.Objective: The purpose of this investigation was to examine the effect of an acute swimming exercise session on nucleotidase activities in rat blood serum. Methods: Male Wistar rats were divided in exercise and sedentary groups. In the exercise group, rats were submitted to one swimming session (60 minutes) with a constant load of 4% of body weight in the tail. Nucleotidase activities were gauged spectrophotometrically by measuring the inorganic phosphate from ATP, ADP or AMP hydrolysis or p-nitrophenol released from of p-Nph-5’- TMP hydrolysis. Results: The exercise group presented a significant increase in nucleoside triphosphate diphosphohydrolase (55.5% and 43.1%, for ATP and ADP, respectively), 5’- nucleotidase (57.4%), and nucleotide pyrophosphatase/phosphodiesterase (24.2%) activities. Conclusion: Our results have shown that nucleotidases are activated in rat blood serum after one session of aerobic swimming exercise, suggesting that these enzymes may promote an increase in adenosine levels, which might contribute to exercise-mediated vasodilatation

Analysis of flavonoids in Rubus erythrocladus and Morus nigra leaves extracts by liquid chromatography and capillary electrophoresis

AbstractThis study uses high performance liquid chromatography and capillary electrophoresis as analytical tools to evaluate flavonoids in hydrolyzed leaves extracts of Rubus erythrocladus Mart., Rosaceae, and Morus nigra L., Moraceae. For phytochemical analysis, the extracts were prepared by acid hydrolysis and ultrasonic bath and analyzed by high performance liquid chromatography using an ultraviolet detector and by capillary electrophoresis equipped with a diode-array detector. Quercetin and kaempferol were identified in these extracts. The analytical methods developed were validated and applied. Quercetin and kaempferol were quantified in R. erythrocladus, with 848.43±66.68μgg−1 and 304.35±17.29μgg−1, respectively, by HPLC-UV and quercetin, 836.37±149.43μgg−1, by CE-DAD. In M. nigra the quantifications of quercetin and kaempferol were 2323.90±145.35μgg−1 and 1446.36±59.00μgg−1, respectively, by HPLC-UV and, 2552.82±275.30μgg−1 and 1188.67±99.21μgg−1, respectively, by CE-DAD. The extracts were also analyzed by ultra-performance liquid chromatography coupled with a diode-array detector and mass spectrometer (MS), UPLC-DAD/MS

HERC Ubiquitin Ligases in Cancer

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies.</jats:p