Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Most human cancers involve multiple genetic changes, including activation of oncogenes such as Ki-ras-2 (Kras2) and inactivation of any one of a number of tumor suppressor genes such as p53 and members of the retinoblastoma (Rb) regulatory axis. As part of an ongoing project to determine how in utero exposure to chemical carcinogens affects the molecular pathogenesis of murine lung tumors, the p53 and p16Cdkn2a genes were analyzed by using paraffin-embedded lung tissues from mice treated transplacentally with 3-methylcholanthrene. Single-strand conformation polymorphism analysis of exons 5-8 of the p53 gene, as well as their flanking introns, demonstrated an absence of mutations at this gene locus. However, a genetic polymorphism was identified at nt 708 in intron 4 of the DBA/2 strain of mice 5 bp downstream of a 3' branching-point splice signal. Analysis of exons 1 and 2 of the Cdkn2a gene by single-strand conformation polymorphism and sequence analyses revealed mutations in exon 2 in 7% of the tumors examined. Tumor 23-1 exhibited a CAC-->TAC transition at nt 301 (His74-->Tyr74), and tumor 36-1 exhibited a GGG-->GAG transition at nucleotide 350 (Gly90-->Glu90). Northern blot analysis of 14 of the larger tumors showed a marked decrease in the levels of Rb RNA expression. Immunohistochemical analysis revealed a spectrum of pRb expression, with the smaller adenomas showing moderate numbers of nuclei with heterogeneous staining for pRb in contrast with a highly reduced or near-complete absence of expression in the nuclei of larger tumors with features of adenocarcinomas. The low incidence of mutations at tumor suppressor loci suggested that inactivation of tumor suppressor genes was a late event in murine lung tumor pathogenesis. The identification of both mutations at the Cdkn2a gene locus and reduced levels of Rb expression combined with previous studies demonstrating a high incidence of mutated Kras2 alleles in these tumors implies that alterations of the Rb regulatory axis, in combination with mutation of Kras2, may be the preferred pathway for the pathogenesis of pulmonary tumors in transplacentally exposed mice.
Mol Carcinog 1998 Mar
PMID:Role of tumor suppressor genes in transplacental lung carcinogenesis. 953 49

GABA[A] receptors in the brain convert binding of GABA (gamma-aminobutyric acid) to inhibition by chloride currents. Several important classes of drugs, including benzodiazepines and alcohol, modulate these receptors, which have also been implicated in epilepsy. We describe the alpha5 subunit of GABAA receptors in mice, comparing inbred DBA/2J mice, prone to juvenile audiogenic seizures, with seizure resistant C57BL/6J mice. We find no sequence differences between the strains, although there are several interesting amino acid differences from the rat. We also compare the expression of the alpha5 subunit in whole brains of DBA/2J mice to that in C57BL/6J mice at 21 days, the peak of the former's seizure susceptibility, again finding no significant difference. We further describe the pattern of expression of alpha5 mRNA during mouse brain development, with a peak at 3 days after birth, and among five brain regions in the adult mouse, with the highest levels in the hippocampus. Finally, we present preliminary evidence for rare alternative splicing of this subunit's message, in the N-terminal extracellular domain, to give a form not translatable into a functional protein.
Brain Res Mol Brain Res 1998 Aug 15
PMID:The alpha5 subunit of the murine type A GABA receptor. 972 94

TCDD, the most potent congener of the polychlorinated dioxins, has been shown to be an antiestrogen. The mechanisms of TCDD-induced antiestrogenicity are still under investigation. In this study, we investigated the effects of TCDD on the expression of the estrogen receptor (ER) gene. We studied the levels of un-spliced ER transcript (hnRNA) as well as the ER mRNA in ovary, uterus and liver of TCDD-treated mice with different genetic backgrounds. To quantitate the ER hnRNA levels, the intron and exon boundary of ER hnRNA was amplified by competitive RT-PCR. The ER mRNA from these mice was quantitated by competitive RT-PCR amplifying exons separated by an intron. ER hnRNA and ER mRNA levels were quantitated 4 days after a single i.p. dose of TCDD (5 microg/kg) in female C57BL/6J (B6) mice, which carry the responsive allele to TCDD. TCDD treatment significantly (p < 0.05) suppressed the levels of ER hnRNA in the ovary (27.4%) and uterus (21.9%). The decreases in ER hnRNA were coordinated with significant (p < 0.01) decreases in ER mRNA in ovary (57.7%) and uterus (37.6%). There was a significant decrease (20.3%, p < 0.05) in liver ER mRNA, however, the changes of ER hnRNA in liver were not significant. The coordinated decreases in ER hnRNA and mRNA in TCDD-treated mice suggest a suppression of transcription of the ER gene. We performed the same study on DBA/2J (D2) mice, which possess the "non-responsive" allele of the aryl hydrocarbon receptor (AhR). These mice demonstrated no significant decrease in either the ER mRNA or hnRNA after TCDD treatment. Overall, these results suggest that TCDD suppresses the gene expression of the ER receptor by decreasing its transcription, and the AhR plays an important role in mediating this response.
J Steroid Biochem Mol Biol 1998 Oct
PMID:Transcriptional suppression of estrogen receptor gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 978 25

Mice of the XVIInc/Z and DBA/2N strains, which are responsive and nonresponsive, respectively, to the aryl hydrocarbon (Ah) receptor, were treated with the hepatocarcinogen 5,9-dimethyldibenzo[c,g]carbazole and their livers were examined by nuclease P1-enhanced 32P-postlabeling for the levels of DNA adducts formed. Pretreatment at the doses usually reported in the literature with the cytochrome P4501A (CYP1A) inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), beta-naphthoflavone (BNF), and isosafrole modulated DNA adduction. In XVIInc/Z mice, DNA adduction was totally inhibited by TCDD (a CYP1A1/1A2 inducer), BNF (a CYP1A1/1A2 inducer), and isosafrole (a CYP1A2 inducer). In DBA/2N mice, in which DNA adduction was also inhibited by TCDD, about 25% of the DNA adduct levels persisted after pretreatment with BNF (not a CYP1A1/1A2 inducer in this strain) or isosafrole (a CYP1A2 inducer in this strain). The increase (in all cases less than twofold) in the levels of the phase-II drug-metabolizing enzymes glutathione S-transferase and uridine diphospho-glucuronyltransferase after treatment with inducers cannot explain the total disappearance of DNA adducts. Assays of 5-bromo-2'-deoxyuridine incorporation did not show any induction of DNA synthesis which could explain the decrease in adducts. These results suggest that in vivo 1) increases in CYP1A enzymes by inducers are not correlated with enhanced levels of certain DNA adducts; and 2) phase-II drug metabolizing enzymes are not the main cellular protection pathway for detoxification. An additional mechanism, perhaps also induced by the Ah receptor but highly dependent on the dose of inducer, could be involved in parallel to multidrug resistance (mdr); further experiments are needed to identify this process used by the cell to enhance its protection against toxic or genotoxic effects.
Environ Mol Mutagen 1998
PMID:Inhibition of 5,9-dimethyldibenzo[c,g]carbazole-DNA adduct formation in mouse liver by pretreatment with cytochrome P4501A inducers in vivo. 988 5

Previous studies appeared to indicate that CYP1B1 was not constitutively expressed in mouse liver. In our laboratory, we demonstrated using aromatic hydrocarbon-responsive receptor knock-out (AHR-(-)/-) mice that both piperonyl butoxide (PBO) and acenaphtyhlene (ACN) are AHR-independent inducers of murine CYP1A2 and CYP1B1 mRNA. In the current study, we demonstrate both constitutive levels and induction of CYP1B1 in mouse liver. The induction of CYP1B1 mRNA by PBO or ACN was higher in DBA/2 (Ahrd) than in C57BL/6 (Ahrb-1) mice, while 3-methylcholanthrene induced CYP1B1 more in C57BL/6 than in DBA/2 mice. These results suggest that CYP1B1 may also be induced by more than one mechanism. In addition, constitutive expression of CYP1B1 was detected in liver, kidney, and lung of untreated C57BL/6 mice. There was no gender difference in CYP1B1 expression; however, in C57BL/6 mice, the kidney contained less CYP1B1 than either liver or lung.
J Biochem Mol Toxicol 1999
PMID:Constitutive expression and induction of CYP1B1 mRNA in the mouse. 1040 58

The TEC-2 epitope is a carbohydrate located on the plasma membrane (oolemma) of the oocyte and appears to be involved in bovine sperm-oolemma fusion. The carbohydrates N-acetylgalactosamine (GalNAc) and galactose are part of the TEC-2 epitope and this study investigated the involvement of these carbohydrates during bovine fertilization. Gametes were exposed to the carbohydrates GalNAc, galactose, and fructose, and the lectins DBA and Con A to determine whether there was an effect on fertilization. The DBA lectin recognizes the carbohydrate GalNAc, whereas Con A recognizes the carbohydrates glucose and mannose. Oocytes pretreated with the DBA lectin prior to fertilization showed a reduction in cleavage corresponding to an increase in lectin concentrations. There was a significant increase in sperm-oolemma binding although fusion was inhibited. Oocytes exposed to GalNAc prior to sperm insemination had no effect on fertilization, however, sperm pretreatment with the carbohydrate caused inhibition of fertilization, with a reduction in cleavage rates as the GalNAc concentration increased. There was also a significant decrease in sperm-oolemma fusion and a significant increase in sperm-oolemma binding. When gametes were exposed to GalNAc at the time of fertilization a similar response to that seen with sperm pretreatment was observed. The carbohydrates galactose and fructose and the lectin Con A did not affect fertilization. In conclusion, the carbohydrate GalNAc, which is associated with the TEC-2 epitope, has a specific role during bovine sperm-oolemma fusion. This study also suggests that there is a carbohydrate-binding molecule on the sperm that binds GalNAc.
Mol Reprod Dev 1999 Oct
PMID:Inhibition of bovine sperm-oocyte fusion by the carbohydrate GalNAc. 1047 78

We studied the kinetics of in vivo nitrite production in the inflammatory reaction induced by M. bovis BCG into the pleural space. Pleural macrophages harvested from C57Bl/6 mice after acute BCG infection produced high levels of nitric oxide (NO). Enhanced production was obtained upon stimulation with LPS plus IFN-gamma. In sharp contrast, macrophages from DBA-2 mice produced low levels of NO, as nitrite, at the same time interval (24 h after BCG infection), being completely refractory to further stimulation. After the third day, NO production was similar in both strains. There was a close relationship between nitrite levels in the pleural exudate in vivo and those produced by harvested macrophages in vitro. In this in vivo system, the pattern of NO production by pleural macrophages one day after BCG infection was discrepant and unexpected in the response of C57Bl/6 and DBA-2 mice. However, this early response did not affect the late progressive NO production in both mice strains, that may be responsible to the late control of the mycobacteria growth.
Int J Mol Med 2000 Jan
PMID:Nitric oxide production by BCG-infected pleural macrophages from C57Bl/6 and DBA-2 mice. 1060 81

Genetic polymorphisms are thought to play an important role in determining susceptibility to neural tube defects (NTDs), for example between different ethnic groups, but the embryonic manifestation of these polymorphic genetic influences is unclear. We have used a mouse model to test experimentally whether polymorphic variations in the pattern of cranial neural tube closure can influence susceptibility to NTDs. The site at which cranial neural tube closure begins (so-called closure 2) is polymorphic between inbred mice. Strains with a caudal location of closure 2 (e.g. DBA/2) are relatively resistant to NTDs, whereas strains with a rostrally positioned closure 2 (e.g. NZW) exhibit increased susceptibility to NTDs. We tested experimentally whether altering the position of closure 2 can affect susceptibility to cranial NTDs, by back- crossing the splotch ( Sp (2H) ) mutant gene onto the DBA/2 background. As a control, Sp (2H) was transferred onto the NZW background, which resembles splotch mice in its closure pattern. Approximately 80% of Sp (2H) homozygotes develop NTDs, both cranial (exencephaly) and spinal (spina bifida). After transfer to the DBA/2 background, the frequency of cranial NTDs was reduced significantly in Sp (2H) homozygotes, confirming a protective effect of caudal closure 2. In contrast, Sp (2H) homozygotes on the NZW background had a persistently high frequency of cranial NTDs. The frequency of spina bifida was not altered in either backcross, emphasizing the specificity of this genetic effect for cranial neurulation. These findings demonstrate that variation in the pattern of cranial neural tube closure is a genetically determined factor influencing susceptibility to cranial NTDs.
Hum Mol Genet 2000 Mar 01
PMID:A genetic risk factor for mouse neural tube defects: defining the embryonic basis. 1069 80

The mouse cpk mutation is the most extensively characterized murine model of polycystic kidney disease (PKD) and closely resembles human autosomal recessive PKD (ARPKD), with the exception that B6-cpk/cpk homozygotes do not express the biliary ductal plate malformation (DPM) lesion. However, homozygous mutants from outcrosses to other strains, e.g. DBA/2J (D2), CD-1, BALB/c and Mus mus castaneus (CAST), express the DPM. The current study was designed: (i) to characterize the cpk-associated biliary disease in affected F(2) homozygotes from intercrosses with either CAST or D2; and (ii) to evaluate focal biliary cysts identified in heterozygotes from a D2-cpk congenic strain. We found that all F(2) cpk/cpk pups expressed both the typical renal cystic disease and the DPM. The DPM severity, assessed using semi-quantitative histopathological analysis, was markedly variable in these F(2) progeny. We found no correlation between the severity of the DPM and the renal cystic disease in either F(2) cohort. In addition, we identified focal cysts, apparently of biliary origin, in the livers of both aged D2-+/cpk and F(1) heterozygotes. Genetic analysis demonstrated loss of heterozygosity at the cpk interval and supports a loss-of-function model for biliary cysts. We conclude that the cpk allele contains an inactivating mutation which disrupts tubulo-epithelial differentiation in the kidney and biliary tract. Expression of the biliary lesion is modulated by genetic background, and the specific biliary phenotype is determined by whether loss of function of the cpk gene occurs as a germline or a somatic event.
Hum Mol Genet 2000 Mar 22
PMID:Germline and somatic loss of function of the mouse cpk gene causes biliary ductal pathology that is genetically modulated. 1074 84

The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a complex genetic trait involving multiple loci, while DBA/2 and C57BL/6 strains are genetically resistant to the plasmacytomagenic effects of pristane. In this model system for human B-cell neoplasia, one of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM) chromosomal region that included Cdkn2a, which encodes p16(INK4a) and p19(ARF), and the coding sequences for the BALB/c p16(INK4a) and p19(ARF) alleles were found to be polymorphic with respect to their resistant Pctr1 counterparts in DBA/2 and C57BL/6 mice (45). In the present study, alleles of Pctr1, Cdkn2a, and D4Mit15 from a resistant strain (BALB/cDAG) carrying DBA/2 chromatin were introgressively backcrossed to the susceptible BALB/c strain. The resultant C.DAG-Pctr1 Cdkn2a D4Mit15 congenic was more resistant to plasmacytomagenesis than BALB/c, thus narrowing Pctr1 to a 1.5-cM interval. Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2a gene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn strain. Biological assays of the p16(INK4a) and p19(ARF) alleles from BALB/c and DBA/2 indicated that the BALB/c p16(INK4a) allele was less active than its DBA/2 counterpart in inducing growth arrest of mouse plasmacytoma cell lines and preventing ras-induced transformation of NIH 3T3 cells, while the two p19(ARF) alleles displayed similar potencies in both assays. We propose that the BALB/c susceptibility/modifier locus, Pctr1, is an "efficiency" allele of the p16(INK4a) gene.
Mol Cell Biol 2001 Jan
PMID:Efficiency alleles of the Pctr1 modifier locus for plasmacytoma susceptibility. 1111 5


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