title: Tumor promotion by caspase-resistant retinoblastoma protein.
abstract: The retinoblastoma (RB) protein regulates cell proliferation and cell death. RB is cleaved by caspase during apoptosis. A mutation of the caspase-cleavage site in the RB C terminus has been made in the mouse Rb-1 locus; the resulting Rb-MI mice are resistant to endotoxin-induced apoptosis in the intestine. The Rb-MI mice do not exhibit increased tumor incidence, because the MI mutation does not disrupt the Rb tumor suppressor function. In this study, we show that Rb-MI can promote the formation of colonic adenomas in the p53-null genetic background. Consistent with this tumor phenotype, Rb-MI reduces colorectal epithelial apoptosis and ulceration caused by dextran sulfate sodium. 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.
authors.affiliation: Division of Hematology/Oncology, Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Helena L
authors.initials: HL
authors.lastname: Borges
authors.forename: Jeff
authors.initials: J
authors.lastname: Bird
authors.forename: Katherine
authors.initials: K
authors.lastname: Wasson
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.forename: Jean Y J
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D016158:Genes, p53; D008223:Lymphoma / Q000209:etiology*; D051379:Mice; D009154:Mutation; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000502:physiology; D013724:Teratoma / Q000209:etiology*
chemical_list: D016160:Retinoblastoma Protein; D020169:Caspases