SERGIO PEREIRA DE ALMEIDA TOLEDO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
4 resultados
Resultados de Busca
Agora exibindo 1 - 4 de 4
- Assessing the emerging oncogene protein kinase C epsilon as a candidate gene in families with Carney complex-2(2012) TOLEDO, Rodrigo A.; SEKIYA, Tomoko; HORVATH, Anelia; FAUCZ, Fabio; FRAGOSO, Maria C. B. V.; LONGUINI, Viviane C.; LOURENCO JR., Delmar M.; TOLEDO, Sergio P. A.; STRATAKIS, Constantine A.
- Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus(2011) COSTA, Marcia Helena Soares; DOMENICE, Sorahia; TOLEDO, Rodrigo Almeida; JUNIOR, Delmar Muniz L.; LATRONICO, Ana Claudia; PINTO, Emilia Modolo; TOLEDO, Sergio Pereira Almeida; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson VillaresBACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the Delta Delta CT method, and beta-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions.
- Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations(2014) LONGUINI, Viviane C.; LOURENCO JR., Delmar M.; SEKIYA, Tomoko; MEIRELLES, Osorio; GONCALVES, Tatiana D.; COUTINHO, Flavia L.; FRANCISCO, Guilherme; OSAKI, Luciana H.; CHAMMAS, Roger; ALVES, Venancio A. F.; SIQUEIRA, Sheila A. C.; SCHLESINGER, David; NASLAVSKY, Michel S.; ZATZ, Mayana; DUARTE, Yeda A. O.; LEBRAO, Maria Lucia; GAMA, Patricia; LEE, Misu; MOLATORE, Sara; PEREIRA, Maria Adelaide A.; JALLAD, Raquel S.; BRONSTEIN, Marcello D.; CUNHA-NETO, Malebranche B.; LIBERMAN, Bernardo; FRAGOSO, Maria Candida B. V.; TOLEDO, Sergio P. A.; PELLEGATA, Natalia S.; TOLEDO, Rodrigo A.Objective: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for. Design: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. Methods: Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression. Results: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are >= 30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors. Conclusions: Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.
- p27 variant and corticotropinoma susceptibility: a genetic and in vitro study(2014) SEKIYA, Tomoko; BRONSTEIN, Marcello D.; BENFINI, Katiuscia; LONGUINI, Viviane C.; JALLAD, Raquel S.; MACHADO, Marcio C.; GONCALVES, Tatiana D.; OSAKI, Luciana H.; HIGASHI, Leonardo; VIANA- JR., Jose; KATER, Claudio; LEE, Misu; MOLATORE, Sara; FRANCISCO, Guilherme; CHAMMAS, Roger; NASLAVSKY, Michel S.; SCHLESINGER, David; GAMA, Patricia; DUARTE, Yeda A. O.; LEBRAO, Maria Lucia; ZATZ, Mayana; MEIRELLES, Osorio; LIBERMAN, Bernardo; FRAGOSO, Maria Candida B. V.; TOLEDO, Sergio P. A.; PELLEGATA, Natalia S.; TOLEDO, Rodrigo A.Germline mutations in p27(kip1) are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population- matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH- secreting pituitary tumors alone or with the sporadic counterpart of MEN2- component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27- V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH- secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.