Molecular Basis of Low-Penetrance Retinoblastoma

Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants

“…Previous studies have indicated that pRB and certain low penetrance pRB mutants may suppress tumorigenesis through a mechanism that is independent of the ability to bind E2F (Harbour, 2001;Kratzke et al, 1994;Otterson et al, 1997Otterson et al, , 1999Sellers et al, 1998). Here, we describe a novel pRB function that may be relevant to this E2F-independent effect.…”

“…Stable binding to E2F was clearly dispensable to the induction of NBs, because each of the non-E2F binding low penetrance pRB mutants promoted NB production. Moreover, the interaction of pRB with histone deacetylases may be dispensable, since NBs were induced by pRB 712R , which is mutated in a region that is important for histone deacetylase association (Harbour, 2001;Otterson et al, 1999). One pRB function that might relate to the increase in NBs is transcriptional coactivation, because the pRB 661W and pRB Dex4 mutants retained coactivator function (Sellers et al, 1998) as well as the ability to increase NB formation.…”

“…One pRB function that is implicated in tumor suppression entails the binding of pRB to E2F and the repression of E2F-responsive genes. However, pRB may have tumor suppressor abilities beyond the regulation of E2F, since several low penetrance RB alleles that retain substantial tumor suppressor function encode proteins with little, if any, E2F binding capacity (Harbour, 2001;Kratzke et al, 1994;Otterson et al, 1997Otterson et al, , 1999Sellers et al, 1998). In addition to their partial tumor suppressor ability, these low penetrance mutants retained the ability of wild type pRB to induce a flat, senescence-like morphology when ectopically expressed in Saos-2 osteosarcoma cells (Sellers et al, 1998;Xu et al, 1997).…”

Retinocitoma: relato de cinco casos

“…A primeira propõe que nos casos de retinocitoma a inativação do segundo alelo do gene RB1 ocorreria num período mais tardio da maturação retiniana, quando a célula precursora afetada teria uma capacidade mitótica reduzida, resultando na formação de uma lesão com características citológicas benignas (5,10) . A segunda hipótese é de que, em famílias com penetrância incompleta, a inativação do segundo alelo resultaria em produto parcialmente funcionante (a proteína que impede o surgimento do tumor) (5,(11)(12) .…”

Molecular biology of prostate cancer

“…If one copy of the gene is already missing because of an inherited defect, then loss of the sole remaining allele results in complete absence of that gene's product, which can lead to a cancer. The loss of both alleles of a gene, termed the 'two-hit' hypothesis by Knudson in 1971, 77 explained the epidemiology of retinoblastoma and loss of the RB gene was later confirmed to be causative [79][80][81][82] (Tables 3 and 4).…”