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Campinas, Brazil

Tamura R.E.,University of Cape Town | de Vasconcellos J.F.,Centro Infantil Boldrini | de Vasconcellos J.F.,University of Campinas | Sarkar D.,Virginia Commonwealth University | And 4 more authors.
Current Molecular Medicine | Year: 2012

The Growth Arrest and DNA Damage-inducible 45 (GADD45) proteins have been implicated in regulation of many cellular functions including DNA repair, cell cycle control, senescence and genotoxic stress. However, the pro-apoptotic activities have also positioned GADD45 as an essential player in oncogenesis. Emerging functional evidence implies that GADD45 proteins serve as tumor suppressors in response to diverse stimuli, connecting multiple cell signaling modules. Defects in the GADD45 pathway can be related to the initiation and progression of malignancies. Moreover, induction of GADD45 expression is an essential step for mediating anti-cancer activity of multiple chemotherapeutic drugs and the absence of GADD45 might abrogate their effects in cancer cells. In this review, we present a comprehensive discussion of the functions of GADD45 proteins, linking their regulation to effectors of cell cycle arrest, DNA repair and apoptosis. The ramifications regarding their roles as essential and central players in tumor growth suppression are also examined. We also extensively review recent literature to clarify how different chemotherapeutic drugs induce GADD45 gene expression and how its up-regulation and interaction with different molecular partners may benefit cancer chemotherapy and facilitate novel drug discovery. © 2012 Bentham Science Publishers. Source


Ghiraldini F.G.,University of Campinas | Silveira A.B.,Centro Infantil Boldrini | Kleinjan D.A.,University of Edinburgh | Gilbert N.,University of Edinburgh | Mello M.L.S.,University of Campinas
BMC Endocrine Disorders | Year: 2014

Background: Hyperglycemia induces chromatin remodeling with consequences on differential gene expression in mouse hepatocytes, similar to what occurs during aging. The liver is the central organ for the regulation of glucose homeostasis and xenobiotic and lipid metabolism and is affected by insulin signaling. The precise transcriptional profiling of the type-1 diabetic liver and its comparison to aging have not been elucidated yet. Methods: Here, we studied the differential genomic expression of mouse liver cells under adult hyperglycemic and aged normoglycemic conditions using expression arrays. Results: Differential gene expression involved in an increase in glucose and impaired lipid metabolism were detected in the type-1 diabetic liver. In this regard, Ppargc1a presents an increased expression and is a key gene that might be regulating both processes. The differential gene expression observed may also be associated with hepatic steatosis in diabetic mouse liver, as a secondary disease. Similarly, middle-aged mice presented differential expression of genes involved in glucose, lipid and xenobiotic metabolism. These genes could be associated with an increase in polyploidy, but the consequences of differential expression were not as drastic as those observed in diabetic animals. Conclusions: Taken together, these findings provide new insights into gene expression profile changes in type-1 diabetic liver. Ppargc1a was found to be the key-gene that increases glucose metabolism and impairs lipid metabolism impairment. The novel results reported here open new areas of investigation in diabetic research and facilitate the development of new strategies for gene therapy. © 2014 Ghiraldini et al.; licensee BioMed Central Ltd. Source


Cardoso B.A.,University of Lisbon | De Almeida S.F.,University of Lisbon | Laranjeira A.B.A.,Centro Infantil Boldrini | Carmo-Fonseca M.,University of Lisbon | And 3 more authors.
Leukemia | Year: 2011

The transcription factor T-cell acute lymphocytic leukemia (TAL)-1 is a major T-cell oncogene associated with poor prognosis in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 binds histone deacetylase 1 and incubation with histone deacetylase inhibitors (HDACis) promotes apoptosis of leukemia cells obtained from TAL1 transgenic mice. Here, we show for the first time that TAL1 protein expression is strikingly downregulated upon histone deacetylase inhibition in T-ALL cells. This is due to decreased TAL1 gene transcription in cells with native TAL1 promoter, and due to impaired TAL1 mRNA translation in cells that harbor the TAL1 d microdeletion and consequently express TAL1 under the control of the SCL/TAL1 interrupting locus (SIL) promoter. Notably, HDACi-triggered apoptosis of T-ALL cells is significantly reversed by TAL1 forced overexpression. Our results indicate that the HDACi-mediated apoptotic program in T-ALL cells is partially dependent on their capacity to downregulate TAL1 and provide support for the therapeutic use of HDACi in T-ALL. © 2011 Macmillan Publishers Limited All rights reserved. Source


Silva A.,Institute Medicina Molecular | Silva A.,UK National Institute for Medical Research | Laranjeira A.B.A.,Centro Infantil Boldrini | Martins L.R.,Institute Medicina Molecular | And 5 more authors.
Cancer Research | Year: 2011

The importance of microenvironmental factors for driving progression in leukemia has been debated. Previous evidence has pointed to interleukin-7 (IL-7), a fundamental cytokine to normal T-cell development and homeostasis, as an important determinant of the viability and proliferation of T-cell acute lymphoblastic leukemia (T-ALL) cells in vitro. In this study, we report that IL-7 is also a critical determinant of T-ALL progression. T-ALL cell lines and primary T-ALL samples initiated leukemia more slowly when engrafted to immunocompromised Rag2-/-IL2rg-/- mice lacking IL-7. This effect was not related to reduced engraftment or homing of transplanted cells to the bone marrow. Instead, IL-7 deficiency diminished expansion of leukemia cells in the bone marrow and delayed leukemia-associated death of transplanted mice. Moreover, infiltration of different organs by T-ALL cells, which characterizes patients with advanced disease, was more heterogeneous and generally less efficient in IL-7-deficient mice. Leukemia progression was associated with increased Bcl-2 expression and cell viability, reduced p27 Kip1 expression, and decreased cell-cycle progression. Clinical measurements of IL-7 plasma levels and IL-7 receptor (IL-7R) expression in T-ALL patients versus healthy controls confirmed that IL-7 stimulates human leukemia cells. Our results establish that IL-7 contributes to the progression of human T-cell leukemia, and they offer preclinical validation of the concept that targeting IL-7/IL-7R signaling in the tumor microenvironment could elicit therapeutic effects in T-ALL. ©2011 AACR. Source


Mendes R.D.,Erasmus University Rotterdam | Sarmento L.M.,University of Lisbon | Cante-Barrett K.,Erasmus University Rotterdam | Zuurbier L.,Erasmus University Rotterdam | And 12 more authors.
Blood | Year: 2014

Phosphatase and tensin homolog (PTEN)-inactivating mutations and/or deletions are an independent risk factor for relapse of T-cell acute lymphoblastic leukemia (T-ALL) patients treated on Dutch Childhood Oncology Group or German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia protocols. Some monoallelic mutated or PTEN wild-type patients lack PTEN protein, implying that additional PTEN inactivation mechanisms exist. We show that PTEN is inactivated by small deletions affecting a few exons in 8% of pediatric T-ALL patients. These microdeletions were clonal in 3% and subclonal in 5% of patients. Conserved deletion breakpoints are flanked by cryptic recombination signal sequences (cRSSs) and frequently have non-template-derived nucleotides inserted in between breakpoints, pointing to an illegitimate RAG recombination-driven activity. Identified cRSSs drive RAG-dependent recombination in a reporter system as efficiently as bona fide RSSs that flank gene segments of the T-cell receptor locus. Remarkably, equivalent microdeletions were detected in thymocytes of healthy individuals. Microdeletions strongly associate with the TALLMO subtype characterized by TAL1 or LMO2 rearrangements. Primary and secondary xenotransplantation of TAL1-rearranged leukemia allowed development of leukemic subclones with newly acquired PTEN microdeletions. Ongoing RAG activitymay therefore actively contribute to the acquisition of preleukemic hits, clonal diversification, and disease progression. © 2014 by The American Society of Hematology. Source

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