RESUMO
A murine homologue of the epithelial membrane protein 2 (EMP2) gene was identified in a search for genes associated with B-cell lymphoma tumorigenicity by using suppression subtractive hybridization. Expression of EMP2 messenger RNA in primary mouse tissues was limited to certain epithelial cell types and the peritoneal lymphoid compartment. EMP2 was expressed in the poorly tumorigenic DAC B-lymphoma cell line but was significantly down-regulated in a subline selected for in vivo tumor formation in Balb/c mice. Recombinant restoration of EMP2 expression in the subline suppressed its tumorigenicity, suggesting that loss of EMP2 was a causal factor in the malignant phenotype. Recombinant overexpression of EMP2 was studied in B lymphoma and NIH3T3 cells. EMP2 in both cell types induced cell death on serum deprivation. EMP2-induced cell death correlated with the expression level of EMP2 protein and was prevented by caspase inhibitors Z-VAD and Z-DEVD. These findings for the first time describe an apoptotic effect of a GAS3 family gene in lymphocytes. They also suggest that EMP2 may influence B-lymphoma tumorigenicity through a functional tumor suppressor phenotype. (Blood. 2001;97:3890-3895)
Assuntos
Linfoma de Células B/genética , Linfoma de Células B/terapia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/farmacologia , Células 3T3/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , DNA Complementar/isolamento & purificação , Células Epiteliais/química , Técnicas de Transferência de Genes , Genes Supressores de Tumor , Terapia Genética , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Fizzy-related (fzr) is a recently identified 7WD domain family member implicated in cell cycle regulation of Drosophila and yeast. In this study, the murine homologue of fzr was isolated by suppression subtractive hybridization as a gene with decreased expression during malignant progression of a murine B-lymphoma cell line. Retroviral overexpression of fzr in B-lymphoma cells reduced tumor formation. Those tumors that did arise had diminished or extinguished retroviral Fzr. Surprisingly, fzr overexpression dramatically increased B-lymphoma cell susceptibility to natural killer cell (NK) cytotoxicity, a host-resistant mechanism for tumor formation in this model system. These findings implicate fzr as a new category of genes suppressing B-cell tumorigenesis and suggest a novel role for fzr in the target cell interaction with NK cells.
