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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.