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The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIr) is required for the activation of transforming growth factor beta, and previously we have found its expression to be significantly reduced in both rat and human hepatocellular carcinomas (HCCs). Therefore, we have postulated that loss of the M6P/IGFIIr gene may be mechanistically involved in liver carcinogenesis. Using the polymerase chain reaction, we utilized two polymorphisms in the 3' untranslated region of the M6P/IGFIIr gene to screen non-cirrhotic, hepatitis virus negative patients with hepatocellular tumors for LOH. Twenty-two of 36 (61%) patients were informative (heterozygous), and 14/22 (64%) liver tumors had LOH; 11/16 (69%) carcinomas, 1/3 (33%) fibrolamellar tumors and 2/3 (67%) adenomas. This is the first report of LOH at the M6P/IGFIIr locus in human hepatocellular tumors, and the presence of LOH in adenomas suggests that allelic loss may be an early event in the etiology of HCCs. These results support the hypothesis that the M6P/IGFIIr gene may function as a tumor suppressor gene in the liver.
NUP116 encodes a 116-kD yeast nuclear pore complex (NPC) protein that is not essential but its deletion (nup116 delta) slows cell growth at 23 degrees C and is lethal at 37 degrees C (Wente, S. R., M. P. Rout, and G. Blobel. 1992. J. Cell Biol. 119:705-723). Electron microscopic analysis of nup116 delta cells shifted to growth at 37 degrees C revealed striking perturbations of the nuclear envelope: a double membrane seal that was continuous with the inner and outer nuclear membranes had formed over the cytoplasmic face of the NPCs. Electron-dense material was observed accumulating between the cytoplasmic face of these NPCs and the membrane seal, resulting in "herniations" of the nuclear envelope around individual NPCs. In situ hybridization with poly(dT) probes showed the accumulation of polyadenylated RNA in the nuclei of arrested nup116 delta cells, sometimes in the form of punctate patches at the nuclear periphery. This is consistent with the electron microscopically observed accumulation of electron-dense material within the nuclear envelope herniations. We propose that nup116 delta NPCs remain competent for export, but that the formation of the membrane seals over the NPCs blocks nucleocytoplasmic traffic.