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At least 739 records · Page 41Linked to original sources
PubMed1996

Adenovirus-mediated transfer of the p53 gene produces rapid and generalized death of human glioma cells via apoptosis.

Wild-type p53 is involved in several aspects of cell cycle control and suppression of transformation, inducing either apoptosis or G1 block in cell cycle progression. Using a recombinant adenovirus containing the wild-type p53 cDNA, the biological effects of the newly expressed wild-type p53 protein were examined in six human glioma cell lines. Three cell lines (U-251 MG, U-373 MG, and A-172) expressed endogenous mutant p53, and the other three (U-87 MG, EFC-2, and D54 MG) expressed wild-type p53. The restoration of normal p53-encoded protein in the mutant cell lines induced apoptosis as assessed by morphological studies using nuclear staining, electron microscopy, and flow cytometric assays. In wild-type p53 cell lines, however, the overexpression of wild-type p53 did not result in apoptosis but inhibited cellular proliferation rather drastically and modified the neoplastic phenotype. Differential effects suggest two pathways for glioma oncogenesis and a possible therapeutic strategy.

Adenoviruses, Human↗
PubMedDate not supplied

Tumor induction and tumor regression in Xiphophorus.

Spontaneous melanoma in hybrids of Xiphophorus is caused by overexpression of the receptor tyrosine kinase gene Xmrk. In rare cases melanoma also occurs in non-hybrid fish from natural habitats where the trigger is unknown. In these tumors Xmrk is overexpressed too, pointing to a similar molecular mechanism underlying neoplastic transformation. After carcinogen treatment a variety of tumor of other histiotypes are induced. Tumor genes other than Xmrk seem to cause these neoplasias. Genetic alterations have been detected in a recently isolated mutant, and immunomodulators, and androgens can cause regression of hybrid melanoma. The variety of etiologies and the multiplicity of exogenous factors and agents that induce cancer or modify the neoplastic phenotype allow the study in Xiphophorus of many of the problems of tumorigenesis found in vivo.

Animals↗
PubMed2001

In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration.

We investigated whether a single plasma midazolam concentration could serve as an accurate predictor of total midazolam clearance, an established in-vivo probe measure of cytochrome P450 3A (CYP3A) activity. In a retrospective analysis of data from 224 healthy volunteers, non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time curves following intravenous (IV) and/or oral administration. Based on statistical moment theory, the concentration at the mean residence time (MRT) should be the best predictor of the total area under the curve (AUC). Following IV or oral midazolam administration, the average MRT was found to be approximately 3.5 h, suggesting that the optimal single sampling time to predict AUC was between 3 and 4 h. Since a 4-h data point was common to all studies incorporated into this analysis, we selected this time point for further investigation. The concentrations of midazolam measured 4 h after an IV or oral dose explained 80 and 91% of the constitutive interindividual variability in midazolam AUC, respectively. The 4-h midazolam measurement was also an excellent predictor of drug-drug interactions involving CYP3A induction and inhibition. Compared with baseline values, the direction and magnitude of change in midazolam AUC and the 4-h concentration were completely concordant for all study subjects. We conclude that a single 4-h midazolam concentration following IV or oral administration represents an accurate marker of CYP3A phenotype under constitutive and modified states. Moreover, the single-point approach offers an efficient means to phenotype and identify individuals with important genetic polymorphisms that affect CYP3A activity.

Administration, Oral↗
PubMed2000

Phenotype assessment: are you missing something?

BACKGROUND AND PURPOSE: Phenotype assessment of genetically modified rodents is an essential component of animal model development and their eventual use. Described here is a paradigm to consider as we collectively pursue phenotype assessment of the constantly increasing number of genetically modified rodent models, as well as those with spontaneously occurring mutations. METHODS: Review of past experiences and the literature provides useful examples to illustrate the principles described. CONCLUSION: A practical approach to phenotype assessment can be divided into a primary level of assessment to find abnormalities, and a secondary level of more specialized assessment to quantify and evaluate the abnormalities detected. There are many subtle, but important phenotypic characteristics that can be markedly affected by the background genetics and environment of the animal being assessed.

Acyl-CoA Dehydrogenase↗
PubMedDate not supplied

Mox: a novel modifier of the tomato Xa locus.

We have isolated a novel mutation that caused variegated leaf color in a tomato plant which had multiple maize Ac transposable elements and the tomato Xa allele. Xa is a previously characterized semi-dominant mutation that causes tomato leaves to be bright yellow when heterozygous (Xa/xa+). The mutation responsible for the new phenotype was named Mox (Modifier of Xa). The Mox mutation modified the Xa/xa+ yellow leaf phenotype in two ways: it compensated for the Xa allele resulting in a plant with a wildtype green color, and it caused somatic variegation which appeared as white and yellow sectors on the green background. Somatic variegation was visible only if the plant contained both the Mox and Xa loci. Genetic studies indicated that the Mox locus was linked in repulsion to Xa and that the Mox locus was genetically transmitted at a reduced frequency through the male gamete. Molecular characterization of the Ac elements in lines segregating for Mox identified an Ac insertion that appeared to cosegregate with Mox variegation. We propose a model in which the Mox mutation consists of a duplication of the xa+ allele and subsequent Ac-induced breakage of the duplicated region causes variegation.

Alleles↗
PubMed1996

Environmental and genetic effects on the asymmetry phenotype: Diazinon resistance in the Australian sheep blowfly, Lucilia cuprina.

The asymmetry phenotype of diazinon-resistant flies lacking a fitness/asymmetry Modifier (+/+; R/-) was dominant and independent of developmental temperature, larval density and diazinon concentration. Asymmetry score, pooled over three bristle characters, was approximately 50% greater for these phenotypes than for those of modified genotypes (M/+; +/+) and unmodified susceptibles (+/+; S/S) reared under standard laboratory conditions. Modified and susceptible phenotypes showed increased asymmetry score for temperatures and larval densities above and below standard rearing conditions; a positive correlation was observed between diazinon concentration and asymmetry score. Single and multiple environmental stresses resulted in similar scores that approached, but never exceeded, those of unmodified resistant phenotypes. Irrespective of the developmental conditions anti-symmetry and fluctuating asymmetry were typically observed for each bristle character of unmodified resistant and the modified and susceptible phenotypes, respectively. Thus while similar asymmetry scores could arise from genetic or environmental effects, asymmetry pattern was genetically based. Population cage analyses at different temperatures and larval densities showed a negative association between mean asymmetry and relative fitness.

Animals↗
PubMed2004

Chromosomal phenotypes and submicroscopic abnormalities.

The finding, during the last decade, that several common, clinically delineated syndromes are caused by submicroscopic deletions or, more rarely, by duplications, has provided a powerful tool in the annotation of the human genome. Since most microdeletion/microduplication syndromes are defined by a common deleted/duplicated region, abnormal dosage of genes located within these regions can explain the phenotypic similarities among individuals with a specific syndrome. As such, they provide a unique resource towards the genetic dissection of complex phenotypes such as congenital heart defects, mental and growth retardation and abnormal behaviour. In addition, the study of phenotypic differences in individuals with the same microdeletion syndrome may also become a treasury for the identification of modifying factors for complex phenotypes. The molecular analysis of these chromosomal anomalies has led to a growing understanding of their mechanisms of origin. Novel tools to uncover additional submicroscopic chromosomal anomalies at a higher resolution and higher speed, as well as the novel tools at hand for deciphering the modifying factors and epistatic interactors, are 'on the doorstep' and will, besides their obvious diagnostic role, play a pivotal role in the genetic dissection of complex phenotypes.

Animals↗
PubMed2003

Characterization of the human glycerol kinase promoter: identification of a functional HNF-4alpha binding site and evidence for transcriptional activation.

Glycerol kinase (GK) is an enzyme at the interface of carbohydrate and fat metabolism. Mutations in the GK gene result in a rare inborn error of metabolism, GK deficiency (GKD), and at least one of these mutations (N288D) is associated with insulin resistance and diabetes mellitus. In an attempt to identify potential modifiers of the GKD phenotype, and to elucidate better the relationship between GKD and diabetes mellitus, we investigated the GK promoter. We examined the GK promoter using in silico methods, transient transfections of GK promoter-luciferase constructs in HepG2 hepatocellular carcinoma cells, and gel shift assays using liver nuclear extracts. We determined that the first 100 bp of the GK 5(') upstream region was sufficient for basal levels of transcription and that there was a functional HNF-4alpha binding site in the first 500 bp of the 5(') upstream region that was important for increased levels of GK expression in vitro. The involvement of both GK and HNF-4alpha in the etiology of diabetes mellitus is intriguing, and we speculate that HNF-4alpha represents a potential modifier of the GKD phenotype.

5' Flanking Region↗
PubMed1986

[Genetic analysis of mitochondrial rho-mutability in Saccharomyces. I. Polygenic determination of spontaneous rho-mutability: gene-modifiers and srm mutation].

The phenotypic trait "starry colony" in Saccharomyces is associated with a high spontaneous rho- petite mutability. Genetic analysis of this trait has shown the high rho- mutability to be caused by several modifying genes present together in the cell genome. Every single modifying gene only produces a relatively small enhancement in the rho- mutability. Mutations in four nuclear srm (spontaneous rho- mutability) loci were isolated after mutagenic treatment of highly rho- mutable haploid cells. In contrast to the modifying genes, each of these mutations has a pronounced effect on the spontaneous rho- mutability, causing significant decrease in it.

DNA, Fungal↗
PubMed2000

A genetic screen for modifiers of a kinase suppressor of Ras-dependent rough eye phenotype in Drosophila.

kinase suppressor of Ras (ksr) encodes a putative protein kinase that by genetic criteria appears to function downstream of RAS in multiple receptor tyrosine kinase (RTK) pathways. While biochemical evidence suggests that the role of KSR is closely linked to the signal transduction mechanism of the MAPK cascade, the precise molecular function of KSR remains unresolved. To further elucidate the role of KSR and to identify proteins that may be required for KSR function, we conducted a dominant modifier screen in Drosophila based on a KSR-dependent phenotype. Overexpression of the KSR kinase domain in a subset of cells during Drosophila eye development blocks photoreceptor cell differentiation and results in the external roughening of the adult eye. Therefore, mutations in genes functioning with KSR might modify the KSR-dependent phenotype. We screened approximately 185,000 mutagenized progeny for dominant modifiers of the KSR-dependent rough eye phenotype. A total of 15 complementation groups of Enhancers and four complementation groups of Suppressors were derived. Ten of these complementation groups correspond to mutations in known components of the Ras1 pathway, demonstrating the ability of the screen to specifically identify loci critical for Ras1 signaling and further confirming a role for KSR in Ras1 signaling. In addition, we have identified 4 additional complementation groups. One of them corresponds to the kismet locus, which encodes a putative chromatin remodeling factor. The relevance of these loci with respect to the function of KSR and the Ras1 pathway in general is discussed.

Amino Acid Sequence↗
PubMed2003

Genetic identification of effectors downstream of Neu (ErbB-2) autophosphorylation sites in a Drosophila model.

The ErbB-2/Neu receptor tyrosine kinase plays a causal role in tumorigenesis in mammals. Neu's carboxyl terminus contains five phosphorylated tyrosines that mediate transformation through interaction with cytoplasmic SH2 or PTB containing adaptor proteins. We show that Drosophila adaptors signal from individual phosphotyrosine sites of rat Neu. Activated Neu expression in the midline glia suppressed apoptosis, similar to that seen with activated Drosophila EGF-R expression. Expression in eye and wing tissues generated graded phenotypes suitable for dosage-sensitive modifier genetics. Suppression of ErbB-2/Neu-induced phenotypes in tissues haplosufficient for genes encoding adaptor protein or second messengers suggests that pTyr 1227(YD) signals require Shc, and that pTyr 1253 (YE) signalling does not employ Ras, but does require Raf function. Signalling from pTyr (YB) was affected by a haplosufficiency in drk (Grb-2), and in genes thought to function downstream of Grb-2: dab, sos, csw (Shp-2), and dos (Gab-1). These data demonstrate the power of Drosophila genetics to unmask the molecules that signal from oncogenic ErbB-2/Neu.

Adaptor Proteins, Vesicular Transport↗
PubMed2000

The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64.

The Mom1 (Modifier of Min-1) region of distal chromosome 4 was identified during a screen for polymorphic modifiers of intestinal tumorigenesis in ApcMin/+ mice. Here, we demonstrate that the Mom1AKR allele consists of two genetic components. These include the secretory phospholipase Pla2g2a, whose candidacy as a Mom1 resistance modifier has now been tested with several transgenic lines. A second region, distal to Pla2g2a, has also been identified using fine structure recombinants. Pla2g2aAKR transgenic mice demonstrate a modest resistance to tumorigenesis in the small intestine and a very robust resistance in the large intestine. Moreover, the tumor resistance in the colon of Pla2g2aAKR animals is dosage-dependent, a finding that is consistent with our observation that Pla2g2a is expressed in goblet cells. By contrast, mice carrying the distal Mom1 modifier demonstrate a modest tumor resistance that is confined to the small intestine. Thus, the phenotypes of these two modifier loci are complementary, both in their quantitative and regional effects. The additive effects and tight linkage of these modifiers may have been necessary for the initial identification of the Mom1 region.

Adenomatous Polyposis Coli↗
PubMed2005

Systematic, RNA-interference-mediated identification of mus-101 modifier genes in Caenorhabditis elegans.

The Mus101 family of chromosomal proteins, identified initially in Drosophila, is widely conserved and has been shown to function in a variety of DNA metabolic processes. Such functions include DNA replication, DNA damage repair, postreplication repair, damage checkpoint activation, chromosome stability, and chromosome condensation. Despite its conservation and widespread involvement in chromosome biogenesis, very little is known about how Mus101 is regulated and what other proteins are required for Mus101 to exert its functions. To learn more about Mus101, we have initiated an analysis of the protein in C. elegans. Here, we show that C. elegans mus-101 is an essential gene, that it is required for DNA replication, and that it also plays an important role in the DNA damage response. Furthermore, we use RNA interference (RNAi)-mediated reverse genetics to screen for genes that modify a mus-101 partial loss-of-function RNAi phenotype. Using a systematic approach toward modifier gene discovery, we have found five chromosome I genes that modify the mus-101 RNAi phenotype, and we go on to show that one of them encodes an E3 SUMO ligase that promotes SUMO modification of MUS-101 in vitro. These results expand our understanding of MUS-101 regulation and show that genetic interactions can be uncovered using screening strategies that rely solely on RNAi.

Animals↗
PubMed2006

Of mice and men: tyrosinase modification of congenital glaucoma in mice but not in humans.

PURPOSE: Primary congenital glaucoma (PCG) is an autosomal recessive ocular trait caused by mutations in the gene for cytochrome P4501B1 (CYP1B1). Although PCG is often considered to be fully penetrant, the disease shows 50% penetrance in some Saudi Arabian families. The familial segregation of the nonpenetrance suggests a genetic modifier. Recently, tyrosinase (Tyr) deficiency was found to worsen the drainage structure/ocular dysgenesis phenotype of Cyp1b1-/- mice, suggesting that Tyr is a modifier of the phenotype. In the current study, tyrosinase (TYR) was investigated in human PCG. METHODS: A genome-wide screen, a single nucleotide polymorphism (SNP) analysis in the TYR chromosomal region 11q13-q21, and sequencing of the TYR gene was performed with individuals from Saudi Arabian families with multiple, clinically confirmed, molecularly proven, nonpenetrant members. RESULTS: The study outcome did not support TYR as a modifier of the PCG phenotype in this population. The sequencing data showed no TYR mutations in the nonpenetrant family members and no difference in polymorphism frequencies between nonpenetrant or fully penetrant families. CONCLUSIONS: TYR is not a modifier of the CYP1B1-associated PCG phenotype in the Saudi Arabian population.

Adolescent↗
PubMed1998

Basic FGF, EGF, and PDGF modify TGFbeta-induction of smooth muscle cell phenotype in human prostatic stromal cells.

BACKGROUND: We investigated the ability of a variety of growth factors to regulate the differentiation of prostatic fibroblasts into smooth muscle cells. METHODS: Smooth muscle actin levels were monitored by immunoblot analysis and immunocytochemistry. Proliferation was measured in clonal growth assays and by cell counts. RESULTS: We determined that TGFbeta inhibited proliferation and induced smooth muscle differentiation of stromal cells derived from prostatic adenocarcinomas, as we previously reported for cells derived from the normal peripheral zone. Basic FGF, EGF, TGFalpha, and PDGF, but not IGF, retinoic acid, 1,25-dihydroxyvitamin D3, or androgen, attenuated induction of differentiation by TGFbeta, by a mechanism apparently unrelated to proliferation. CONCLUSIONS: Regulation of growth and differentiation occurs equivalently in prostatic stromal cells derived from adenocarcinomas and normal peripheral zone. TGFbeta is a potent inducer of the smooth muscle phenotype. Basic FGF, EGF and/or TGFalpha, and PDGF attenuate TGFbeta's activity, and promote a fibroblastic phenotype. Our studies provide an in vitro model system in which fibroblastic or smooth muscle cells can be promoted, maintained, and investigated in a defined manner. The results suggest that the ratio of fibroblasts to smooth muscle cells in the stroma reflects the relative levels of growth factors, which may be altered in diseased states.

Actins↗
PubMed2003

Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation.

We investigated the role of thrombophilic mutations as possible modifiers of the clinical phenotype in severe factor VII (FVII) deficiency. Among 7 patients homozygous for a cross-reacting material-negative (CRM-) FVII defect (9726+5G>A, FVII Lazio), the only asymptomatic individual carried FV Leiden. Differential modulation of FVII levels by intragenic polymorphisms was excluded by a FVII to factor X (FX) gene haplotype analysis. The coagulation efficiency in the FV Leiden carrier and a noncarrier was evaluated by measuring FXa, FVa, and thrombin generation after extrinsic activation of plasma in the absence and presence of activated protein C (APC). In both patients coagulation factor activation was much slower and resulted in significantly lower amounts of FXa and thrombin than in a normal control. However, more FXa and thrombin were formed in the plasma of the patient carrying FV Leiden than in the noncarrier, especially in the presence of APC. These results were confirmed in FV-FVII doubly deficient plasma reconstituted with purified normal FV or FV Leiden. The difference in thrombin generation between plasmas reconstituted with normal FV or FV Leiden gradually decreased at increasing FVII concentration. We conclude that coinheritance of FV Leiden increases thrombin formation and can improve the clinical phenotype in patients with severe FVII deficiency.

Adult↗
PubMed2001

Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability.

Mutations in the androgen receptor (AR) gene result in a wide range of phenotypes of the androgen insensitivity syndrome (AIS). Inter- and intrafamilial differences in the phenotypic expression of identical AR mutations are known, suggesting modifying factors in establishing the phenotype. Two 46,XY siblings with partial AIS sharing the same AR gene mutation, R846H, but showing very different phenotypes are studied. Their parents are first cousins. One sibling with grade 5 AIS was raised as a girl; the other sibling with grade 3 AIS was raised as a boy. In both siblings serum levels of hormones were measured; a sex hormone-binding globulin (SHBG) suppression test was completed; and mutation analysis of the AR gene, Scatchard, and SDS-PAGE analysis of the AR protein was performed. Furthermore, 5alpha-reductase 2 expression and activity in genital skin fibroblasts were investigated, and the 5alpha-reductase 2 gene was sequenced. The decrease in SHBG serum levels in a SHBG suppression test did not suggest differences in androgen sensitivity as the cause of the phenotypic variation. Also, androgen binding characteristics of the AR, AR expression levels, and the phosphorylation pattern of the AR on hormone binding were identical in both siblings. However, 5alpha-reductase 2 activity was normal in genital skin fibroblasts from the phenotypic male patient but undetectable in genital skin fibroblasts from the phenotypic female patient. The lack of 5alpha-reductase 2 activity was due to absent or reduced expression of 5alpha-reductase 2 in genital skin fibroblasts from the phenotypic female patient. Exon and flanking intron sequences of the 5alpha-reductase 2 gene showed no mutations in either sibling. Additional intragenic polymorphic marker analysis gave no evidence for different inherited alleles for the 5alpha-reductase 2 gene in the two siblings. Therefore, the absent or reduced expression of 5alpha-reductase 2 is likely to be additional to the AIS. Distinct phenotypic variation in this family was caused by 5alpha-reductase 2 deficiency, additional to AIS. This 5alpha-reductase deficiency is due to absence of expression of the 5alpha-reductase iso-enzyme 2 as shown by molecular studies. The distinct phenotypic variation in AIS here is explained by differences in the availability of 5alpha-dihydrotestosterone during embryonic sex differentiation.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗