Suppression of the neoplastic phenotype by replacement of the Tsc2 gene in Eker rat renal carcinoma cells.

The hereditary renal carcinoma (RC) in the rat, originally reported by R. Eker in 1954, is an excellent example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Recently, we have identified a germline mutation of the sclerosis (Tsc2) gene in the Eker rat (Nature Genetics 9, 70-74, 1995), suggested to be a novel tumor suppressor gene, fitting Knudson's two-hit hypothesis.

Presence of potent transcriptional activation domains in the predisposing tuberous sclerosis (Tsc2) gene product of the Eker rat model.

The Eker rat hereditary renal carcinoma is an excellent example of Mendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis gene (TSC2) gives rise to dominantly inherited cancer in the Eker rat model, as well as a tumor suppressor nature for the Tsc2 gene function. We also showed a strong conservation between the rat and human gene products.

Molecular diagnosis of hepatitis C viral infection.

With the evolution of confirmatory assays for hepatitis C viral infections, bulk populations of unknown hepatitis were diagnosed as hepatitis C virus (HCV)-mediated chronic liver dysfunction throughout the world. More recently, several systems for molecular diagnosis of hepatitis C viral infections were developed. These are commonly performed for efficient antiviral therapy using interferon.

Cloning of the rat homologue of the von Hippel-Lindau tumor suppressor gene and its non-somatic mutation in rat renal cell carcinomas.

Recently, von Hippel-Lindau (VHL) gene mutations were detected in non-inherited, sporadic human renal cell carcinomas (RCs) at a high frequency. In order to determine whether or not the VHL gene is also a critical gene in rat RCs, we cloned and sequenced the rat homologue of human VHL gene and searched for mutations of the VHL gene in rat RCs. Mutations in the VHL gene were not detected in spontaneous RCs of the Eker rat model or in ferric nitrilotriacetate-induced rat RCs using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method.

Isolation of cDNA clone encoding human homologue of senescence marker protein-30 (SMP30) and its location on the X chromosome.

We have isolated and characterized a cDNA clone encoding human homologue of senescence marker protein-30 (SMP30), a calcium binding protein also called regucalcin (RC). This clone (pHSMP6) has 1356 base pairs (bp) and contains an open reading frame of 897 bp, which encodes 299 amino acids. The estimated molecular weight of the deduced polypeptide is 33,250 and pI is 5.

Allelic loss at the tuberous sclerosis (Tsc2) gene locus in spontaneous uterine leiomyosarcomas and pituitary adenomas in the Eker rat model.

Hereditary renal carcinomas (RCs) develop in virtually all Eker rats by the age of one year. Investigation of extra-renal primary tumors co-occurring in Eker rats late in life (at 2 years) additionally revealed enhanced development of hemangiosarcomas of the spleen, uterine leiomyosarcomas and pituitary adenomas, although the demonstrated predilection for these extra-renal tumors was not as complete as with RCs. We identified the germline mutated tuberous sclerosis (Tsc2) gene as the predisposing Eker gene and revealed the tumor suppressor nature of Tsc2 gene function in renal carcinogenesis.

Molecular genetic basis of renal carcinogenesis in the Eker rat model of tuberous sclerosis (Tsc2).

We have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in the Eker rat. The homozygous mutant condition is lethal at around the 13th day of fetal life. In heterozygotes, RCs invariably develop in the first year of life.

cDNA structure, alternative splicing and exon-intron organization of the predisposing tuberous sclerosis (Tsc2) gene of the Eker rat model.

The Eker rat hereditary renal carcinoma (RC) is an excellent example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis gene (TSC2) gives rise to the dominantly inherited cancer in the Eker rat model. We now describe the entire cDNA (5375 bp without exons 25 and 31) and genomic structure of the rat Tsc2 gene.

Early detection of Knudson's two-hits in preneoplastic renal cells of the Eker rat model by the laser microdissection procedure.

Hereditary renal cell carcinomas invariably develop by the age of 1 year in Eker rats. At the histological level, renal cell carcinomas develop through multiple stages from early preneoplastic lesions (e.g.

Genomic instability involved in virus-related hepatocarcinogenesis.

In spite of the epidemiological link between the hepatitis C virus (HCV) infection and the incidence of hepatocellular carcinoma (HCC), there is currently no data to prove the direct oncogenicity of HCV. In this situation, we must consider not only the viral but also the nonviral factor which may accelerate hepatocarcinogenesis. Previously, we showed that a 60-bp subgenomic HBV DNA (15AB, nt 1555-1914 of HBV DNA) is a hot spot for the genomic recombination, and the cellular protein binding to 15AB may be the putative recombinogenic protein.

A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer.

The Eker rat hereditary renal carcinoma (RC) is an excellent example of a mendelian dominant predisposition to a specific cancer in an experimental animal. We have previously established a new conserved linkage group on rat chromosome 10q and human chromosome 16p13.3, and shown that the Eker mutation is tightly linked to the tuberous sclerosis (Tsc2) gene.

Renal carcinogenesis in the Eker rat.

The Eker rat hereditary renal carcinoma is an excellent example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis (TSC2) gene gives rise to the dominantly inherited cancer in the Eker rat model. The function of the TSC2/Tsc2 gene product (called "tuberine" in the human case) is not yet understood, although it contains a short amino acid sequence homologous to the ras family GTPase-activating proteins (GAP3).

Hepatocarcinogenesis in rodents and humans.

In hepatocarcinogenesis in rodents, induction of foci and nodules comprising clonally proliferated initiated cells is considered to be essential for the future development of carcinomas. Nodules in human cirrhotic liver, though known to be associated with a high hepatocellular carcinoma risk, have generally been regarded as regenerative in nature, and not the result of clonal or neoplastic cell proliferation, on a morphological basis. However, when we analyzed 83 cirrhotic nodules from 11 HBV carrier patients, utilizing hepatitis B virus (HBV) integration as a marker for clonal proliferation, we found the existence of clonal populations of more than 10(5) hepatocytes in 26 (31.

Isolation of genes differentially expressed between the Yoshida sarcoma and long-survival Yoshida sarcoma variants: origin of Yoshida sarcoma revisited.

The Yoshida sarcoma (YS) is characterized by growth as "free cells" in ascites. Long-survival Yoshida sarcoma (LY) variants, which develop after transplantation of YS into immunologically conditioned Donryu rats, in contrast, form "islands" in ascites. A representational difference analysis (RDA) approach was adopted to isolate genes differentially expressed between YS and LY variants to elucidate the molecular mechanism of their development.

The predisposing gene of the Eker rat inherited cancer syndrome is tightly linked to the tuberous sclerosis (TSC2) gene.

The Eker rat is a promising animal model of cancer predisposition syndromes. In this study, using 129 backcross animals, we have established a new conserved linkage group on rat 10q and human 16p13.3 whereby the Eker mutation was found to be tightly linked to the tuberous sclerosis (TSC2) gene.

A novel cancer predisposition syndrome in the Eker rat model.

Hereditary renal carcinomas (RCs) develop in virtually all Eker rats by the age of one year. Investigation of extrarenal primary tumors occurring in Eker rats late in life (at 2 years) additionally revealed pituitary adenomas (17/31 = 54.8% (carrier) vs 7/32 = 21.

Determination of a putative recombinogenic human hepatitis B virus sequence and its binding cellular protein.

Previously, we reported that C4BglII196, a 196-base pair subgenomic fragment of hepatitis B virus (HBV) covering its precore region, enhances in vitro recombination in the presence of extracts from actively dividing cells (Hino, O., et al. Proc.

Subcutaneous sarcomas of probable neuronal origin in a transgenic mouse strain containing an albumin promoter-fused simian virus 40 large T antigen gene.

Frequent development of subcutaneous neurogenic sarcomas was observed in a hepatocellular carcinoma-producing transgenic mouse strain harboring an albumin-promoted simian virus 40 (SV40) large T antigen gene. Found unexpectedly in 19 out of 306 mice (6.2%) by 6 months of age, all the sarcomas were similar and were characterized as neurogenic on the basis of histological features including Homer-Wright type rosette formation, the presence of dense core granules of 100-200 nm diameter under the electron microscope, expression of neuron specific enolase, S-100 protein, and catecholamines, and nerve cell-like differentiation in culture in response to But2cAMP.

Allelic loss at the predisposing gene locus in spontaneous and chemically induced renal cell carcinomas in the Eker rat.

Hereditary renal carcinoma (RC) in the rat, originally reported by Eker in 1954, is an example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. We previously reported that ionizing radiation induces additional tumors in a linear dose-response relationship, suggesting that in heterozygotes two events (one inherited, one somatic) are necessary to produce tumors. Recently, the predisposing gene has been mapped to rat chromosome 10.

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Interferon-gamma may play an important role in the immune response and in inflammatory diseases, including chronic active hepatitis. To understand the role of interferon-gamma in the regulation of inflammation and to establish a mouse model of chronic active hepatitis, we produced transgenic mice in which the mouse interferon-gamma gene was regulated by a liver-specific promoter, the serum amyloid P component gene promoter. Four transgenic mouse lines were generated, and two of these lines expressed mRNA of interferon-gamma in the liver.

Hepatitis virus-related hepatocarcinogenesis.

We propose that hepatitis virus can cause an increase in the incidence of liver cancer by a combination of two mechanisms: (1) cell killing and stimulation of mitosis leading to an accumulation of events necessary for transformation, and (2) an increase in chromosomal instability mediated by induced recombinogenic protein(s) during chronic hepatitis.

Genetic predisposition to transplacentally induced renal cell carcinomas in the Eker rat.

N-Ethyl-N-nitrosourea-induced transplacental renal carcinogenesis in the rat results primarily in Wilms' tumors, apparently because primitive nephroblasts are the preferred target. Our question is whether N-ethyl-N-nitrosourea-induced mutations in the fetal kidney would increase the number of adult-type renal cell carcinomas in the Eker rat, which is heterozygous for a mutation that predisposes to renal cell carcinoma. Surprisingly, renal cell tumors but no Wilm's tumors began to appear from as early as 1 week after birth.