Navegando por Palavras-chave "ubiquitin-proteasome system"

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    The kinin B-1 receptor regulates muscle-specific E3 ligases expression and is involved in skeletal muscle mass control
    (Portland Press Ltd, 2014-08-01) Parreiras-e-Silva, Lucas T.; Reis, Rosana I.; Santos, Geisa A.; Pires-Oliveira, Marcelo [UNIFESP]; Pesquero, Joao B. [UNIFESP]; Gomes, Marcelo D.; Godinho, Rosely O. [UNIFESP]; Costa-Neto, Claudio M.; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)
    Regulation of muscle mass depends on the balance between synthesis and degradation of proteins, which is under the-control of different signalling pathways regulated by hormonal, neural and nutritional stimuli. Such stimuli are altered in several pathologies, including COPD (chronic obstructive pulmonary disease), diabetes, AIDS and cancer (cachexia), as well as in some conditions such as immobilization and aging (sarcopenia), leading to muscle atrophy, which represents a significant contribution to patient morbidity. the KKS (kallikrein kinin system) is composed of the enzymes kallikreins, which generate active peptides called kinins that activate two G-protein-coupled receptors, namely B-1 and B-2, which are expressed in a variety of tissues. the local modulation of the KKS may account for its participation in different diseases, such as those of the cardiovascular, renal and central nervous systems, cancer and many inflammatory processes, including pain. Owing to such pleiotropic actions of the KKS by local modulatory events and the probable fine-tuning of associated signalling cascades involved in skeletal muscle catabolic disorders [for example, NF-kappa B (nuclear factor kappa B) and PI3K (phosphoinositide 3-kinase)/Akt pathways], we hypothesized that KKS might contribute to the modulation of intracellular responses in atrophying skeletal muscle. Our results show that kinin B-1 receptor activation induced a decrease in the diameter of C2C12 myotubes, activation of NF-kappa B, a decrease in Akt phosphorylation levels, and an increase in the mRNA levels of the ubiquitin E3 ligases atrogin-1 and MuRF-1 (muscle RING-finger protein-1). in vivo, we observed an increase in kinin B-1 receptor mRNA levels in an androgen-sensitive model of muscle atrophy. in the same model, inhibition of the kinin B-1 receptor with a selective antagonist resulted in an impairment of atrogin-1 and MuRF-1 expression and I kappa B (inhibitor of NF-kappa B) phosphorylation. Moreover, knockout of the kinin B-1 receptor in mice led to an impairment in MuRF-1 mRNA expression after induction of LA (levator ani) muscle atrophy. in conclusion, using pharmacological and gene-ablation tools, we have obtained evidence that the kinin B-1 receptor plays a significant role in the regulation of skeletal muscle proteolysis in the LA muscle atrophy model.
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    Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma
    (Impact Journals Llc, 2017) Pereira Eugenio, Angela Isabel [UNIFESP]; Fook-Alves, Veruska Lia [UNIFESP]; de Oliveira, Mariana Bleker [UNIFESP]; Fernando, Rodrigo Carlini [UNIFESP]; Zanatta, Daniela B.; Strauss, Bryan Eric; Regis Silva, Maria Regina [UNIFESP]; Porcionatto, Marimelia Aparecida [UNIFESP]; Braga Colleoni, Gisele Wally [UNIFESP]
    HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment. Bioluminescence imaging was used to follow tumor response. Treatment with bortezomib showed similar to 60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed similar to 60% of cell death after treatment with VER155008 (alone or with bortezomib). RPMI8226-LUC-PURO xenograft presented tumor reduction by bioluminescence imaging after treatment with bortezomib, VER155008 or drug combination compared to controls. Treatment with bortezomib, alone or combined with VER155008, showed inhibition of tumor growth assessed by bioluminescence imaging after one week in both RPMI8226-LUC-PURO and U266-LUC-PURO cell lines when compared to controls. In conclusion, our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro (late apoptosis induction) and in vivo (inhibition of tumor growth) with special benefit in U266-LUC-PURO, bearing 17p deletion.