Factores ambienciais (Chernobyl) e genéticos na cancerização da tireóide Mut germinativas Mut somáticas BRAF1 RET/PTC SDHD2 e SDHB3 GRIM-194 Mut5 e del6 mtDNA Alterações mitocondriais 1Soares et al, 2003 2Lima et al, 2003 3Lima et al, submitted 4Máximo et al, 2005 5Máximo et al, 2002 6Lima et al, sumbitted

A cadeia respiratória mitocondrial SDHA – doenças degenerativas SDHB, C e D – neoplasias hereditárias

Alterações do DNA mitocondrial em tumores da tireóide Hürthle: mitochondrion rich Mitochondrial DNA large deletions and complex rearrangements in patients with post-Chernobyl thyroid tumours Jorge Lima, Valdemar Máximo, Paula Soares, Gerry A. Thomas, Tatyana Bogdanova, Dillwyn Williams, Manuel Sobrinho-Simões

Alterações de genes nucleares que codificam proteínas da cadeia respiratória mitocondrial em tumores humanos Br J Cancer, 2005 J Clin Endoc Metab, 2003 High frequency of unreported pathogenic germline SDHB mutations in sporadic head and neck paragangliomas from Northern Spain: Structural-functional consequences on mitochondrial complex II and clinico-pathological features. Jorge Lima, Talia Feijao, Isabel Pereira-Castro, Gregorio Fernandez-Ballester, Valdemar Maximo, Agustin Herrero, Luis Serrano, Manuel Sobrinho-Simoes, Ginesa Garcia-Rostan

A cadeia respiratória mitocondrial

Hipótese de trabalho hypoxia GRIM-19 ROS SDH mtDNA HIF1α ELONGIN B Fumarate Mitochondria Succinate ROS SDH mtDNA Succinate HIF1α OH OH ELONGIN B CUL 2 ELONGIN C VHL … E3 Ubiquitin Ligase Complex Cytosol hypoxia PHD - Neurofibromatosis is an autosomal dominant disorder characterized particularly by cafe-au-lait spots and fibromatous tumors of the skin. Other features are variably present - Several young children with some features of NF1 and hematological malignancies have been identified with homozygous mutations in the mismatch repair genes MLH1 and MSH2 HIF1α HIF1α HIF1β Transcription Glucose metabolism Angiogenesis ECM modification Motility Survival P300 Nucleus

ND1 COI SDHB GRIM-19 CytB ATP6 Estratégia GRIM-19 e SDHB: RNAi ND1, CytB, COI e ATP6: cybrid cell lines

IPATIMUP Roswell Park Cancer Institute