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FESBE 2007. Resumo da conferencista #3 e coordenadora do módulo temático intitulado “Reguladores do Ciclo Celular no Desenvolvimento e Câncer: Velhos Parceiros, Novas Funções”. The Two faces of RB: Tumor Promotion by a Tumor Suppressor. Helena Lobo Borges ([email protected],br). Departamento de Anatomia, Instituto de Ciências Biomédicas da UFRJ, Rio de Janeiro, Brasil. Recent findings about the gene mutated in the childhood cancer retinoblastoma, RB gene, will be discussed. Rb was the first tumor suppressor gene to be cloned. Children that inhered one copy of Rb mutated present 9095% chance of developing the retinal tumor before 5 years old. The RB protein regulates cell proliferation, differentiation and apoptosis. The best know function of RB is its ability of blocking the cell cycle progression, a function in agreement with its tumor suppressor function. In a proliferating cell, cyclin-dependent protein kinases hyperphosphorylate RB to inactivate its blocking ability. The mechanism by which RB inhibits cell proliferation is well established. RB interacts with E2F to repress transcription of genes critical for cell cycle progression. Homozygous knockout of Rb gene in mice exhibits embryonic lethality, inappropriate cell cycle entry and massive apoptosis in the developing central nervous system (CNS), peripheral nervous system, lens, liver and muscles. In wild-type cells, RB protein is cleaved by proteases called caspase during apoptosis. A mutation of the caspase-cleavage site in the RB C terminus domain has been made in the mouse Rb-1 locus; the resulting Rb-MI mice are resistant to inflammation- induced apoptosis in the intestine. These results show that RB inhibits cell death in vivo. In cell culture conditions and in vitro, RB was found to bind to a number of cellular proteins. This binding is known to be inhibitory, as it is to nuclear Abl tyrosine kinase, a kinase that can stimulate apoptosis induced by inflammatory stress in cell cultures. In order to investigate the role Abl in the excessive apoptosis in the RB-null mice, we intercrossed Rb+/- and Abl+/- mice to generate double heterozygous Rb+/- Abl+/- mice. The compound Rb+/- Abl+/- were then intercrossed in a large-scale mating, collecting a total of 1029 embryos between E10 and E14.5. The incidence of cell death was evaluated in several embryonic tissues among genotypes. We have shown that the genetic ablation of Abl can reduce apoptosis in the developing central nervous system and the embryonic liver. These results provide in vivo evidence for the pro-apoptotic function of Abl and are consistent with the inhibitory interaction between RB and Abl previously identified in vitro. Since RB showed anti-apoptotic function, a function that might be associated to cancer promotion, we decide to investigate whether RB contribute to tumor formation. RB- resistant to caspases (RB-MI) showed to be resistant to inflammation triggered cell death in intestine. The Rb-MI mice do not exhibit increased tumor incidence, because the MI mutation does not disrupt the Rb tumor suppressor function (inhibition of proliferation). We showed that Rb-MI promote the formation of colonic adenomas in the p53-null genetic background, a tumor suppressor gene found mutated in 50% of human cancers. Consistent with this tumor phenotype, Rb-MI reduces colorectal epithelial apoptosis and ulceration caused by dextran sulfate sodium, a substance used to trigger colon inflammation in mice. By contrast, Rb-MI does not affect the lymphoma phenotype of p53-null mice, in keeping with its inability to protect thymocytes and splenocytes from apoptosis. The Rb-MI protein is expressed and phosphorylated in the tumors, thereby inactivating its growth suppression function. These results suggest that RB tumor suppressor function, i.e., inhibition of proliferation, is inactivated by phosphorylation, whereas RB tumor promoting function, i.e., inhibition of apoptosis, is inactivated by caspase cleavage.