RESUMO
Fumarate hydratase (FH) is an enzyme of the mitochondrial tricarboxylic acid cycle (TCAC). Here we report the characterization of a novel FH variant (FHv) that contains an alternative exon 1b, thus lacking the mitochondrial signal sequence. Distinct from mitochondrial FH, FHv localized to cytosol and nucleus and lacked FH enzyme activity. FHv was expressed ubiquitously in human fetal and adult tissues. Heat shock and prolonged hypoxia increased FHv expression in a cell line (HTB 115) by nine- and fourfold, respectively. These results suggest that FHv has an alternative function outside the TCAC related to cellular stress response.
Assuntos
Fumarato Hidratase/genética , Regulação da Expressão Gênica , Estresse Fisiológico/genética , Sequência de Bases , Western Blotting , Linhagem Celular , DNA Complementar , Imunofluorescência , Humanos , Dados de Sequência Molecular , Biossíntese de Proteínas , Frações Subcelulares/enzimologiaRESUMO
Germline mutations in the fumarate hydratase (FH) gene were recently shown to predispose to the dominantly inherited syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is characterized by benign leiomyomas of the skin and the uterus, renal cell carcinoma, and uterine leiomyosarcoma. The aim of this study was to identify new families with FH mutations, and to further examine the tumor spectrum associated with FH mutations. FH germline mutations were screened from 89 patients with RCC, skin leiomyomas or ovarian tumors. Subsequently, 13 ovarian and 48 bladder carcinomas were analyzed for somatic FH mutations. Two patients diagnosed with ovarian mucinous cystadenoma (two out of 33, 6%) were found to be FH germline mutation carriers. One of the changes was a novel mutation (Ala231Thr) and the other one (435insAAA) was previously described in FH deficiency families. These results suggest that benign ovarian tumors may be associated with HLRCC.
Assuntos
Cistadenoma Mucinoso/genética , Fumarato Hidratase/genética , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/genética , Carcinoma de Células Renais/genética , Cistadenocarcinoma Mucinoso/genética , Feminino , Genes Dominantes , Humanos , Neoplasias Renais/genética , Leiomioma/genética , Masculino , Neoplasias/genética , Neoplasias Cutâneas/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers.
Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Haplótipos , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-mdm2/genética , Fator de Transcrição Sp1/metabolismo , População Branca , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Ligação Proteica , Receptores de Estrogênio/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population-based series of early onset (< or = 45 years) ULMSs. Eighty-one cases were identified through the national cancer registry, and samples from 67 cases (83%) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely.