Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-alpha (TGF-alpha) is a multifunctional cell regulatory protein with a wide range of effects on cell growth and differentiation and has been implicated in the neoplastic transformation of a variety of cell types. Altered expression of TGF-alpha and its cognate receptor (epidermal growth factor receptor) is enhanced in human and rat renal cell carcinomas. The objective of the study reported here was to determine whether altered TGF-alpha expression is an early or late event in renal tubular oncogenesis. The immunohistochemical expression of TGF-alpha was studied in preneoplastic renal tubular lesions in a rat model of hereditary renal cell carcinoma. Strong TGF-alpha immunoreactivity was present at all stages of renal cell tumor development, including the earliest detectable dysplasias. In contrast, the non-neoplastic regenerating tubular epithelium of rat degenerative nephropathy did not stain for TGF-alpha, although this tissue exhibited a proliferative capacity similar to that observed in the dysplastic and neoplastic lesions. This study indicated that altered TGF-alpha expression was detectable early in the development of renal cell tumors and may be an important feature of the transformed phenotype.
Mol Carcinog 1997 Jul
PMID:Altered expression of transforming growth factor-alpha: an early event in renal cell carcinoma development. 925 88

Histologic, nick end labeling for apoptosis and electron microscopic studies were made of the heart, kidney and small intestine in spontaneously hypertensive rats (SHR) treated for 12 weeks with doxorubicin (1 mg/kg/week), mitoxantrone (0.5 or 0.25 mg/kg/week) or saline (controls). Semiquantitative scoring showed that the severity of the cardiac lesions produced by doxorubicin was comparable to that resulting from 0.5 mg/kg mitoxantrone, but greater than that induced by 0.25 mg/kg mitoxantrone (to which it is therapeutically equivalent). The nephropathy and the intestinal toxicity produced by doxorubicin were also more severe than those resulting from either dose of mitoxantrone. Apoptosis of cardiac myocytes was not induced by either drug, but involved cardiac dendritic cells in SHR given doxorubicin. Apoptosis in renal tubular epithelium was comparable in SHR given doxorubicin and the higher dose of mitoxantrone. Doxorubicin induced more frequent apoptosis in intestinal epithelium than did the higher dose of mitoxantrone. We also show that mitoxantrone and iron(III) form a strong 2:1 complex, in which the drug may be acting as a tridentate ligand. This complex, like the iron(III)-doxorubicin complex, may be capable of redox cycling and producing reactive oxygen intermediates (ROI) that damage tissue. Decreased formation of ROI by mitoxantrone may account for its reduced cardiotoxicity compared to that of doxorubicin.
J Mol Cell Cardiol 1997 Sep
PMID:Comparison of the structural changes induced by doxorubicin and mitoxantrone in the heart, kidney and intestine and characterization of the Fe(III)-mitoxantrone complex. 929 65

Hepatocyte growth factor/scatter factor (HGF/SF) is a potent mitogen, motogen, and morphogen for epithelial cells expressing its tyrosine kinase receptor, the c-met proto-oncogene product, and is required for normal development in the mouse. Inappropriate stimulation of Met signal transduction induces aberrant morphogenesis and oncogenesis in mice and has been implicated in human cancer. NK1 is a naturally occurring HGF/SF splice variant composed of only the amino terminus and first kringle domain. While the biological activities of NK1 have been controversial, in vitro data suggest that it may have therapeutic value as an HGF/SF antagonist. Here, we directly test this hypothesis in vivo by expressing mouse NK1 in transgenic mice and comparing the consequent effects with those observed for mice carrying an HGF/SF transgene. Despite robust expression, NK1 did not behave as an HGF/SF antagonist in vivo. Instead, NK1-transgenic mice displayed most of the phenotypic characteristics associated with HGF/SF-transgenic mice, including enlarged livers, ectopic skeletal-muscle formation, progressive renal disease, aberrant pigment cell localization, precocious mammary lobuloalveolar development, and the appearance of mammary, hepatocellular, and melanocytic tumors. And like HGF/SF-transgenic livers, NK1 livers had higher levels of tyrosine-phosphorylated complexes associated with Met, suggesting that the mechanistic basis for the effects of NK1 overexpression in vivo was autocrine activation of Met. We conclude that NK1 acts in vivo as a partial agonist. As such, the efficacy of NK1 as a therapeutic HGF/SF antagonist must be seriously questioned.
Mol Cell Biol 1998 Mar
PMID:NK1, a natural splice variant of hepatocyte growth factor/scatter factor, is a partial agonist in vivo. 948 42

Nail-patella syndrome (NPS) is an inherited developmental disorder most commonly involving maldevelopment of the fingernails, kneecaps and elbow joints. NPS exhibits wide variation in phenotypic expression within and among families with respect to these features. Other skeletal abnormalities such as hip dislocation and club foot have also been reported in some individuals with NPS. There is an association between NPS and renal disease, and between NPS and open-angle glaucoma (OAG), but it is not known whether mutations in a single gene cause the observed skeletal, renal and ophthalmic abnormalities. Recently, LMX1B , a transcription factor of the LIM-homeodomain type with homologs that are important for limb development in vertebrates, was mapped to the same general location as NPS at 9q34. We sequenced a large segment of LMX1B from the genomic DNA of probands from four families with NPS and OAG, and identified four mutations: two stop codons, a deletion causing a frameshift and a missense mutation in a functionally important residue. The presence of these putative loss-of-function mutations in the DNA of individuals with NPS indicates that haploinsufficiency of LMX1B underlies this disorder. These findings help to explain the high degree of variability in the NPS phenotype, and suggest that the skeletal defects in NPS are a result of the diminished dorsoventral patterning activity of LMX1B protein during limb development. The results further suggest that the NPS and OAG phenotypes in the families studied result from mutations in a single gene, LMX1B.
Hum Mol Genet 1998 Jul
PMID:Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome. 961 65

Fumonisin B1 is a mycotoxin produced by Fusarium moniliforme, a common fungus in corn. It is known to cause a variety of diseases, including hepatic and renal degeneration in many species of laboratory and domestic animals. The known biochemical events in fumonisin B1 toxicity involve inhibition of ceramide synthase leading to disruption of sphingolipid metabolism. The effect of fumonisin B1 on ceramide and more complex sphingolipids in mice is not known. Groups of five male BALB/c mice each were injected with fumonisin B1 subcutaneously at doses of 0, 0.25, 0.75, 2.25, and 6.75 mg/kg body weight daily for 5 days. This protocol has been shown to produce a dose-dependent increase in apoptosis in liver and kidney of these animals. In the present study, liver, kidney, and brain were sampled and analyzed for free sphingoid bases and complex sphingolipids one day after the last treatment. A dose-related accumulation of free sphinganine and sphingosine was observed in liver and kidney, but not brain. The maximal increase in free sphinganine in kidney was 10-fold greater than in liver. Total phospholipids increased only in liver, whereas ceramide levels were not consistently altered in liver, kidney, or brain. In liver and kidney, fumonisin B1 treatment increased the sphinganine-containing complex sphingolipids, but no effect was observed on sphingosine-containing complex sphingolipids. No changes in complex sphingolipids were observed in brain. In liver, there was a close correlation between the extent of free sphinganine accumulation, and apoptosis and hepatopathy. This correlation was also evident in kidney but to a lessor extent. Nonetheless, the apoptosis and nephropathy occurred with little or no change in the levels of ceramide or more complex sphingolipids.
J Biochem Mol Toxicol 1998
PMID:Early fumonisin B1 toxicity in relation to disrupted sphingolipid metabolism in male BALB/c mice. 966 34

Mycoplasma fermentans is a likely causative agent of HIV-associated nephropathy. In a pilot study, M. fermentans DNA was detected with polymerase chain reaction (PCR) in urine samples from renal allograft recipients; nine (39.1%) out of 23 renal allograft recipients (most of whom had chronic allograft rejection) and none of the 20 controls, were infected with M. fermentans. A cross-sectional study was conducted to investigate the prevalence of M. fermentans in urine samples from renal allograft recipients. Midstream urine samples were centrifuged at 13,000 x g, purified with QIAamp and tested with PCR using RW004/RW005 and an internal control to screen for the presence of inhibitors. Of the 264 participants recruited, 263 completed the questionnaire (172 men, 92 women); 53 had chronic renal allograft rejection, 106 had chronic renal dysfunction without rejection, 69 had a normal renal allograft for more than 3 months and 35 had a renal allograft for less than 3 months. All urine samples yielded positive results for the internal control. Mycoplasma fermentans DNA was detected once i prospectively collected urine samples. The only individual infected with M. fermentans was also seropositive for HIV-1. This study demonstrates that M. fermentans can be at most sporadically detected in urine from patients living with a renal allograft but is not implicated in chronic rejection of allograft.
Mol Cell Probes 1998 Aug
PMID:Mycoplasma fermentans DNA is infrequently detected in urine specimens from renal transplant recipients. 972 95

Protective protein/cathepsin A (PPCA) is a pleiotropic lysosomal enzyme that complexes with beta-galactosidase and neuraminidase, and possesses serine carboxypeptidase activity. Its deficiency in man results in the neurodegenerative lysosomal storage disorder galactosialidosis (GS). The mouse model of this disease resembles the human early onset phenotype and results in severe nephropathy and ataxia. To understand better the pathophysiology of the disease, we compared the occurrence of lysosomal PPCA mRNA and protein in normal adult mouse tissues with the incidence of lysosomal storage in PPCA(-/-) mice. PPCA expression was markedly variable among different tissues. Most sites that produced both mRNA and protein at high levels in normal mice showed extensive and overt storage in the knockout mice. However, this correlation was not consistent as some cells that normally expressed high levels of PPCA were unaffected in their storage capability in the PPCA(-/-) mice. In addition, some normally low expressing cells accumulated large amounts of undegraded products in the GS mouse. This apparent discrepancy may reflect a requirement for the catalytic rather than the protective function of PPCA and/or the presence of cell-specific substrates in certain cell types. A detailed map showing the cellular distribution of PPCA in nomal mouse tissues as well as the sites of lysosomal storage in deficient mice is critical for accurate assessment of the effects of therapeutic interventions.
Hum Mol Genet 1998 Oct
PMID:Lack of PPCA expression only partially coincides with lysosomal storage in galactosialidosis mice: indirect evidence for spatial requirement of the catalytic rather than the protective function of PPCA. 973 81

Ochratoxin A (OTA) is a mycotoxin which has been detected in foods of plant origin, in edible animal tissues, and in human sera, urine, and milk in many countries. OTA is nephrotoxic and carcinogenic in mice and rats and is suspected to play a key role in the etiology of Balkan endemic nephropathy and/or associated urinary tract tumors. In the present study, some early signs of genetic impairment, including the presence of DNA adducts in target tissues from the progeny of mice after administration of a single OTA dose during late pregnancy, have been investigated. By the 32P-postlabeling method, several characteristic DNA adducts with the same Rf values were detected in kidney and liver of both the OTA-treated mice and their progeny the fetus and the offspring. No adduct was found in tissues from control animals. Different adducts were most important in kidney and liver DNA and some were organ-specific. High levels of DNA adducts were detected in the kidneys of male progeny, whereas in the female progeny and the mothers they were detected almost exclusively in the liver. This result correlates well with the carcinogenicity in mice: the target organ for males is the kidney, while for females it is the liver. High levels of DNA adducts were also found in fetuses. These results provide evidence for a direct genotoxic action of OTA in the progeny through transplacental contamination, which constitutes a new serious health hazard of exposure to this toxin.
Environ Mol Mutagen 1998
PMID:Formation of DNA adducts in tissues of mouse progeny through transplacental contamination and/or lactation after administration of a single dose of ochratoxin A to the pregnant mother. 977 78

Ochratoxin A (OTA), a nephrotoxic and carcinogenic mycotoxin, is implicated in the etiology of Balkan endemic nephropathy (BEN), a chronic disease affecting populations in the Balkans. Patients suffering from Balkan endemic nephropathy, urinary-tract tumors, or both are more frequently extensive metabolizers of debrisoquine than persons unaffected by these conditions. As shown previously (Castegnaro et al., Int J Cancer, 77:70-75, 1998), OTA induction of renal tumors is markedly sex- and strain-specific in Dark Agouti (DA) and Lewis rats, with DA males being most responsive and DA females being resistant; only DA females were phenotyped as slow debrisoquine metabolizers. Formation of OTA-related DNA adducts in the kidney was closely correlated with renal carcinogenicity. To elucidate the critical biotransformation enzymes involved in OTA genotoxicity and carcinogenicity, the expression of cytochrome P450s (CYPs) 1A, 2A, 2B, 2C, 2D, and 3A in the kidney and liver microsomes of untreated and OTA-treated DA and Lewis rats (both sexes) was determined by western blot analysis. Chronic OTA treatment was found to modify CYP expression in kidney and liver. In the animals most susceptible to renal OTA carcinogenicity and DNA adduct formation, the OTA-toxifying isoforms (CYPs 2C11, 1A2, and 3A) were highly expressed in the liver, and little of the OTA-detoxifying isoforms (CYPs 1A1 and 2A) was detected. CYP2D was not expressed in DA rats and therefore is not involved in these phenomena. Our results confirm that the strain- and sex-specific genotoxic response of OTA is controlled, in part, by CYP-mediated metabolic reactions that convert OTA into DNA-reactive intermediates.
Mol Carcinog 1998 Oct
PMID:Sex- and strain-specific expression of cytochrome P450s in ochratoxin A-induced genotoxicity and carcinogenicity in rats. 980 61

Advanced glycation endproducts (AGEs) have been implicated in the pathophysiology of coronary heart disease in ageing, diabetes and renal disease. Competitive enzyme-linked immunosorbent assays (ELISAs) have been developed to measure these compounds in serum, but as recognition of AGEs is both carrier protein- and antibody-dependent standardisation is problematic. We report here on another barrier to standardization, as yet unrecognised. During the development of an AGE ELISA, we found that serum samples did not dilute in parallel to AGE standards or each other. This finding was confirmed by recovery studies that showed over-recovery of AGEs at high serum concentrations, but under-recovery at high dilutions of serum in assay buffer. We developed an inhibition assay to detect factors in serum capable of interacting directly with AGEs immobilised on microtitre plates. Binding of these factors prevented recognition of AGEs by a CML monoclonal antibody and a polyclonal anti-AGE antibody, and was neither sugar- nor carrier protein-dependent. We detected the presence of this factor in all human sera tested and also in foetal calf serum. Pre-incubation of sera with AGEs or heat-treatment at 56 degrees C for 30 min. significantly reduced this binding. We are currently investigating the nature of this factor and the possibility that it may be complement. The effect of this factor on immunoassays for AGEs can only be detected by performing parallelism and recovery studies and we suggest the use of the method referred to in this paper to aid interpretation of parallelism data.
Cell Mol Biol (Noisy-le-grand) 1998 Nov
PMID:Factors in human serum interfere with the measurement of advanced glycation endproducts. 984 89


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