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M Gariboldi

Publications and source records attributed to M Gariboldi.

At least 37 records · Page 2Linked to original sources
PubMed1997

Genetic mapping of lung cancer modifier loci specifically affecting tumor initiation and progression.

Mouse inbred strains with inherited predisposition and resistance to lung cancer provide a tool for the dissection of the complex genetics of this disease. In the present report, we have crossed the BALB/c with the SWR/J strain and performed whole-genome scanning for loci affecting lung tumor development in their F2 progeny. Both parental strains carry the pulmonary adenoma susceptibility 1 (Pas1) locus, a major locus affecting predisposition to lung cancer in mice. On distal chromosome 18 and on centromere of chromosome 6, we have mapped two pulmonary adenoma resistance loci (Par2 and Par4, respectively), which reduce lung tumor multiplicity strongly, up to 15-fold. Par2 and Par4, however, do not affect lung tumor size, which is instead controlled by an additional locus that we have mapped on the central region of chromosome 4. We designated this locus as "pulmonary adenoma progression 1" (Papg1), because it specifically modifies lung tumor size but not multiplicity. The present results, therefore, provide evidence for the existence of cancer modifier loci acting on specific stages of lung tumorigenesis.

Adenoma↗
PubMed1997

Pas1 is a common lung cancer susceptibility locus in three mouse strains.

Inherited predisposition to lung cancer is a phenotypic trait shared by different mouse inbred strains that show either a high or an intermediate predisposition. Other strains are instead genetically resistant. The Pas1 locus is the major determinant of lung cancer predisposition in the A/J strain (Gariboldi et al. 1993). To define the determinants of susceptibility to lung tumorigenesis in the highly susceptible SWR/J and in the intermediately susceptible BALB/c mice, we analyzed (BALB/c x SWR/J)F2 and (BALB/c x C3H/He)F2 crosses by genetic linkage experiments. The present results provide unequivocal evidence that the same Pas1/+ allele that leads to lung cancer predisposition is shared by A/J, SWR/J, and BALB/c strains. The intermediate susceptibility of the BALB/c strain would result by interaction of Pas1 locus with lung cancer resistance loci.

Animals↗
PubMed1996

Genetic mapping of a pulmonary adenoma resistance (Par1) in mouse.

Lung cancer, a major cause of death in the Western world, has a poor prognosis. So far, therapeutic strategies have had only a limited effect. Lung cancer risk is strongly associated with cigarette smoking and lung cancer pedigrees are rare. However, a possible polygenic nature of inherited predisposition to this cancer has been envisaged. Mouse inbred strains with inherited predisposition and resistance to lung cancer provide an important tool for the dissection of the genetics of this complex disease. The A/J strain carries the pulmonary adenoma susceptibility 1 (Pas1) locus and develops many lung tumours. We have mapped the M. spretus-derived locus that strongly resists the lung tumorigenesis in Pas1/+ mice. This locus, pulmonary adenoma resistance 1 (Par1) maps to mouse chromosome 11, near the Rara locus, with a lod score of 5.3. In Pas1/+ mice Par1 accounts for 23% of the phenotypic variance and 10 fold reduction in total tumour volume. These results provide evidence for a major resistance locus affecting the expression of an inherited predisposition to lung cancer.

Adenoma↗
PubMed1996

Stimulation of 5-HT1A receptors in the dorsal hippocampus and inhibition of limbic seizures induced by kainic acid in rats.

1. We studied whether the stimulation of 5-HT1A receptors by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a specific 5-HT1A receptor agonist, reduced electroencephalographic (EEG) seizures induced by intrahippocampal injection of 0.04 microgram in 0.5 microliter of the glutamate analogue kainic acid in freely-moving rats. 2. Pretreatment with 8-OH-DPAT 15 min earlier at the same site as kainic acid injection, caused a dose-dependent decrease of kainic acid-induced seizure activity. One and 10 micrograms significantly reduced the total time spent in seizures by 72% on average and the total number of seizures by 58% (P < 0.01) and 43% (P < 0.05) respectively. The latency to onset of the first seizure was increased 2.8 times (P < 0.01) only after 1 microgram 8-OH-DPAT; 0.1 microgram was ineffective on all seizure parameters. 3. Systemic administration of 25, 100 and 1000 micrograms kg-1 8-OH-DPAT significantly reduced the total number of seizures and the total time in seizures induced by intrahippocampal kainic acid by 52% and 74% on average. The latency to onset of the first seizure was delayed 1.8 times by 100 and 1000 micrograms kg-1 (P < 0.05). 4. The anticonvulsant action of 8-OH-DPAT given intrahippocampally or systemically was significantly blocked by 5 micrograms, but not 1 microgram WAY 100635, a selective 5-HT1A receptor antagonist, administered in the hippocampus before the agonist. 5. These results indicate that postsynaptic 5-HT1A receptors in the hippocampus mediate the anticonvulsant action of 8-OH-DPAT and that their stimulation has an inhibitory role in the generation of limbic seizures.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Neuropeptides-immunoreactivity and their mRNA expression in kindling: functional implications for limbic epileptogenesis.

Recent studies have demonstrated that neuropeptide expression in forebrain neurons is responsive to changes in physiological activity. This is particularly true in the hippocampus where the expression of various neuropeptides has been reported to change in distinct neuronal populations in response to seizure activity. The aim of this work is to review and integrated the information on the pathological changes and functional modifications in neuropeptide systems of the hippocampal formation in kindling and other models of limbic epilepsy. This will be done by presenting a study in which we investigated the changes in the expression of somatostatin, neuropeptide Y (NPY), neurokinin B (NKB) and cholecystokinin-octapeptide (CCK) in the rat hippocampal principal neurons during and after kindling of the hippocampus using immunocytochemistry and in situ hybridization analysis of mRNA. NPY-IR was transiently expressed in the granule cells/mossy fibres after the preconvulsive stage 2 and 2 days but not 1 week after three consecutive tonic-clonic seizures (stage 5). A more pronounced increase was observed in NKB-IR lasting 1 week after kindling acquisition. Only the NKB mRNA expression was enhanced in granule cells at these intervals. At stages 2 and 5, somatostatin- and NPY-IR and their mRNA levels were markedly increased in interneurons in the deep hilus and in the polymorphic cell layer and their presumed projections to the outer molecular layer of the dentate gyrus. NKB- and CCK-IR and their mRNAs were highly expressed in basket cells at both stages of kindling. Their IR was increased in the inner molecular layer of the dentate gyrus in the ventral hippocampus. Peptide-containing neurons in the hilus appeared well preserved in spite of a reduction of Nissl stained cells by 24 % in the stimulated and contralateral hippocampus at stage 5. In the hippocampus proper, somatostatin and NPY-IR were enhanced in the stratum lacunosum molecular while CCK-IR fibres and its mRNA were particularly expressed in the pyramidal cell layer. The number of Somatostatin-, NKB- and CCK-IR cells was increased in the subiculum. The intensity of these changes was similar 2 days after stages 2 or 5 of kindling. Less pronounced effects were observed 1 week after kindling completion. These results, in the frame of the literature data, suggest that lasting functional changes occur in distinct neuropeptide-containing neurons during limbic epileptogenesis. This may have profound effects on synaptic transmission and contribute to modulate hippocampal excitability.

Animals↗
PubMed1995

Different susceptibility to lung tumorigenesis in mice with an identical Kras2 intron 2.

The A/J mouse strain is genetically susceptible to pulmonary tumorigenesis. We have performed a genetic linkage analysis to map pulmonary adenoma susceptibility (Pas) loci in an urethane-treated (A/J x Mus spretus) x C57BL/6J (ASB) interspecific testcross. In this interspecific cross we have confirmed our previous results in AC3F2 mice on the mapping of the Pas1 locus to the distal region of chromosome 6, near Kras2 (Nature Genetics 3: 132-136, 1993). The A/J and M. spretus strains differed at the Pas1 locus, with the M. spretus providing the resistant allele. In the latter strain, we studied the nucleotide sequence of a portion of the second intron of Kras2 that contains polymorphisms associated with lung tumor susceptibility in several inbred strains. The lung tumor-resistant M. spretus strain had the same specific nucleotide sequence of susceptible strains. Mutations in codon 61 of Kras2 in urethane-induced lung tumors from ASF1 hybrids involved the A/J allele in all cases, while the M. spretus allele was never affected. Our results indicate that the M. spretus and A/J mice have an identical structure of the second intron of the Kras2 gene, but they differ in genetic susceptibility to pulmonary tumorigenesis and in mutability of their Kras2 allele.

Analysis of Variance↗
PubMed1995

Analysis of loss of heterozygosity in murine hepatocellular tumors.

Because allelotype analysis of tumors has been important in the identification of new tumor suppressor genes, here we studied loss of heterozygosity (LOH) in a well-defined animal experimental system. We analyzed spontaneous liver tumors from C3HHc x C57BL/6J (B6C3F1) mice and urethane-induced hepatocellular tumors from (C3H/He x Mus spretus) x C57BL/6JBy (HSB) interspecific mice. A total of 95 different genetic markers were tested: 13 in 24 B6C3F1 tumors, 76 in 58 HSB tumors, and six in both groups. Minisatellite finger-printing analysis detected one case of LOH and less than 1% genomic rearrangements in polymorphic and nonpolymorphic bands, respectively. There were no changes at hepatocellular susceptibility loci or at markers homologous to loci frequently lost in human hepatocellular carcinomas. Therefore, our results suggest that LOH and genomic rearrangements are uncommon in mouse hepatocellular tumors.

Alleles↗
PubMed1995

Genetic mapping and expression analysis of the murine DNA ligase I gene.

We mapped the murine DNA ligase I gene (Lig1) in the mouse genome by using a mapping panel from an interspecific cross. Lig1 mapped to a centromeric part of chromosome 7, a region homologous to human chromosome 19q, where the human homologue LIG1 was localized. In addition, Lig1 expression was analyzed during the course of mouse liver-cell regeneration induced by partial hepatectomy, necrogenic doses of carbon tetrachloride, or the mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. The results demonstrate that Lig1 is expressed in the liver during active cell proliferation.

Animals↗
PubMed1995

Mapping of the Hmg1 gene and of seven related sequences in the mouse.

The High Mobility Group 1 protein (HMG1) is an abundant and highly conserved chromosomal protein. Mouse HMG1 is encoded by the Hmg1 gene, containing four introns, but the murine genome contains many related sequences that are mostly retrotransposed pseudogenes. By using an interspecific cross, we have mapped the functional Hmg1 gene on mouse Chromosome (Chr) 5 and seven Hmg1-related sequences on Chrs 6, 8, 17, 18, and X.

Animals↗
PubMed1995

Chromosome mapping of nine tropomyosin-related sequences in mice.

Tropomyosins are a group of actin-binding proteins expressed as different isoforms in muscle and non-muscle cells. Two tropomyosin loci have already been mapped in the mouse genome, on Chromosomes (Chrs) 6 and 9. By using a human cDNA fragment of tropomyosin non-muscle isoform (TPM3) gene that maps on human Chr 1q, and a mapping panel from a murine interspecific cross, we mapped nine distinct tropomyosin-related loci in the mouse genome, on seven different chromosomes: Chrs 3, 4, 6, 7, 14, 17, and X.

Animals↗
PubMed1995

Mapping of body weight loci on mouse chromosome X.

Inheritance of overweight in humans appears to be under polygenic control. Study on the mouse model may help to determine candidate regions in human genome for the search of overweight genes. Inbred mouse strains showed wide variation in body weight and can provide an experimental model for the study of inheritance of overweight. By genetic linkage analysis, we report the mapping of two loci, named Bw1 and Bw2 (body weight 1 and 2), on Chromosome (Chr) X that strongly affect adult body weight in two interspecific testcross male populations (HSB) and ASB) of mice. In addition, another locus, named Bw3, is also mapped on Chr X in ASB populations. These loci account for up to 24% of the phenotypic variation in both populations. Considering the conserved synteny between mouse and humans Chr X, these results provide candidate regions on Chr X that can be tested for linkage with overweight in humans.

Animals↗
PubMed1995

Genetics of liver tumor susceptibility in mice.

A good experimental model of genetic predisposition to hepatocellular tumors is the murine strain C3H. These tumors share morphologic similarities with human hepatocellular tumors. After a treatment with a single small dose of chemical carcinogen, the C3H mice show a high susceptibility to the growth of hepatocellular neoplastic lesions, that reach a volume > 100-fold as compared to the corresponding lesions of genetically resistant strains. Genetic linkage analysis experiments were conducted in 2 different crosses, with the C3H as one of the parental strains, and the other parental strains being represented by mice genetically resistant to hepatocarcinogenesis (A/J, M. spretus). Six different regions, on chromosomes 2, 5, 7, 8, 12, and 19 showed a significant linkage with hepatocellular tumor development. These results provide the genetic basis for the strain variations seen in susceptibility to hepatocarcinogenesis, indicating polygenic inheritance of this trait.

Animals↗
PubMed1994

Multiple loci affect genetic predisposition to hepatocarcinogenesis in mice.

The C3H/He mouse represents a good experimental model of genetic predisposition to hepatocellular tumor development. We analyzed an interspecific test-cross population of 106 urethane-treated male (C3H/He x Mus spretus) x C57BL/6J mice, typed with 222 genetic markers to locate precisely the hepatocellular tumor susceptibility (Hcs) loci. Three regions, on chromosomes 2, 5, and 19, showed a significant linkage with hepatocellular tumor development, as indicated by different quantitative indexes estimating liver tumor size. Liver tumor frequency was not genetically controlled. These loci are different from three other Hcs loci that we have previously mapped in an F2 progeny of the C3H/He mouse crossed with the resistant laboratory strain A/J. The present result indicates a multigenic model of inheritance for hepatocellular tumor susceptibility.

Animals↗
PubMed1994

Comparative mapping of the actin-binding protein 280 genes in human and mouse.

Two genes encode actin-binding protein 280 isoforms. ABP-280 or filamin (FLN1) is present in the cytoskeleton of many cell types, whereas expression of FLN2 is limited to skeletal muscle and heart. FLN1 maps to human chromosome Xq28, and, by physical mapping in YAC clones, we have mapped the homologous murine locus (Fln1) to mouse chromosome X, in a region of syntenic homology with human chromosome X. We mapped FLN2 to human chromosome 7q32-q35 by analysis of somatic cell hybrids containing portions of chromosome 7, and, by using a mapping panel from an interspecific murine cross, we mapped the corresponding murine locus (Fln2) to murine chromosome 6 in a region homologous to human chromosome 7.

Animals↗
PubMed1994

Expression in lung tumors and genetic mapping of the novel murine protein kinase C eta.

Protein kinase C eta (nPKC eta) is a member of the protein kinase C family with a unique tissue distribution in skin and lung. We analyzed nPKC eta expression in normal murine lung and in 36 lung tumors induced by urethane in AC3 F1 and F2 mice. The nPKC eta-related transcript was present at fivefold to tenfold lower levels in tumors than in normal lung controls. We mapped two distinct loci for nPKC eta on murine chromosome 12, using linkage analysis in an interspecific test cross. The results indicate that the mouse Pkcn-rs1 and Pkcn-rs2 loci were about 30 cM from the centromere and about 2 cM from each other.

Animals↗
PubMed1994

The daunorubicin-binding protein of Mr 54,000 is an aldehyde dehydrogenase and is down-regulated in mouse liver tumors and in tumor cell lines.

A rabbit antiserum developed against purified rat liver daunorubicin-binding protein of M(r) 54,000 (DNR-BP54) cross-reacted with a mouse protein of the same molecular weight. This protein was expressed in the liver and several other organs of mice. A series of tumors and cell lines tested for the presence of the protein were negative. By immunocytochemistry, we found that DNR-BP54 was abundantly expressed in the cytoplasm of normal hepatocytes but was expressed at much lower levels in urethane-induced mouse liver tumors. By immunoscreening of a mouse liver cDNA library, we cloned the cDNA coding for DNR-BP54 and we found that this protein is aldehyde dehydrogenase-2 (EC 1.2.1.3). This result was confirmed by the dehydrogenase activity found in pure preparations of DNR-BP54 from normal rat and mouse livers, assayed with acetaldehyde as substrate and NAD as cofactor. The enzyme activity was inhibited by daunorubicin. The inhibition was found to be competitive with respect to NAD.

Aldehyde Dehydrogenase↗