Requirement for a functional Rb-1 gene in murine development

Abstract

Human retinoblastomas can occur both as hereditary and as sporadic cases. Knudson's proposal that they result from two mutational events, of which one is present in the germ line in hereditary cases, has been confirmed by more recent molecular analysis, which has shown both events to involve loss or mutational inactivation of the same gene, RB-1 (ref. 2). RB-1 heterozygosity also predisposes to osteosarcoma, and RB-1 allele losses are seen in sporadic lung, breast, prostate and bladder carcinomas. RB-1 is expressed in most, if not all, tissues and codes for a nuclear phosphoprotein which becomes hypophosphorylated in the G0 growth arrest state and in the G1 phase of the cell cycle. To gain a further insight into the role of RB-1 we and other groups have generated mice carrying an inactivated allele of the homologous gene, Rb-1 (ref. 10), by gene targeting. We report here that young heterozygous mice do not appear abnormal and do not develop retinoblastoma at a detectable frequency. However, homozygous mutant embryos fail to reach term and show a number of abnormalities in neural and haematopoietic development. Broadly similar results are reported by the other groups.

GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells

“…Although F5-5 cells do not express gsc mRNA, even following activin treatment (data not shown), forced expression of gsc via stable transfection inhibited activin-induced di erentiation. Rb7/7 mice and our F5-5 cells transfected with antisense Rb construct show defects in erythroblast di erentiation (Clarke et al, 1992;Jacks et al, 1992;Lee et al, 1992; Figure 2a). Immunoprecipitation of F5-5 lysates with anti-Rb antibodies coprecipitated a *40 kDa protein, whose levels decreased in response to activin and it was re-immunoprecipitated with anti-PU.1 antibodies (Figure 2b,c).…”

“…In Rb-de®cient mice (Clarke et al, 1992;Jacks et al, 1992;Lee et al, 1992) erythroid precursors show defects in terminal di erentiation. We therefore asked if Rb is involved in activin-induced di erentiation of F5-5 cells.…”

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

“…Although such a possibility can not be excluded for Rb, it was recently reported that ectopic expression of DRb is not su cient to induce apoptosis (Janicke et al, 1996;Tan et al, 1997). There is strong evidence that Rb can exert a potent antiapoptotic activity: Rb-de®cient cells are more sensitive to apoptosis than cells expressing Rb (Berry et al, 1996;Clarke et al, 1992;Fan et al, 1996;Jacks et al, 1992;Lee et al, 1992), and the production of viral oncoproteins such as E1A and E7, which inhibit Rb by binding to the B pocket, enhances susceptibility to apoptosis (Howes et al, 1994;Rao et al, 1992). In addition to Rb cleavage, TGFb-mediated apoptosis was always associated with a large decrease of total Rb expression consistent with Rb having a protective e ect ( Figure 5).…”

Modeling human lung cancer in mice: similarities and shortcomings

“…Mice heterozygous and homozygous de®cient for p53 (Donehower et al, 1992;Jacks et al, 1994) and p16 INK4a (Serrano et al, 1996) are viable and have shortened lifespans due to the predominant occurrence of lymphomas and a variety of sarcomas. Mice heterozygous de®cient for Rb have shortened lifespans due to the growth of pituitary tumors, and homozygous Rb de®ciency causes embryonic death (Jacks et al, 1992;Lee et al, 1992;Clarke et al, 1992). Although the incidence of lung cancer is not increased in the p53, p16 INK4a and Rb mutant mice, one group demonstrated bronchiolar neuroendocrine cell hyperplasia in mice homozygous de®cient for p53 and heterozygous de®cient for Rb .…”