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PubMed2004

Differential and opposing regulation of PAI-1 promoter activity by estrogen receptor alpha and estrogen receptor beta in endothelial cells.

To investigate the molecular mechanisms involved in the estrogen-dependent control of plasminogen activator inhibitor-1 (PAI-1) gene expression in vascular cells, we compared the transactivation properties of estrogen receptors (ERalpha and ERbeta) in regulating the activity of a human PAI-1 promoter reporter construct in transfected bovine aortic endothelial cells (BAECs). ERalpha increased PAI-1 promoter activity in BAECs by an estrogen-dependent mechanism, whereas ERbeta suppressed PAI-1 promoter activity by an estrogen-independent mechanism. The suppressive activity of ERbeta was dominant over the inductive activity of ERalpha. Mutation of a putative estrogen response element (ERE) located at position -427 in the proximal promoter abolished the ERalpha action without influencing the suppressive effects of ERbeta. Mutation of either AP1-like site did not eliminate the ERalpha or ERbeta actions at the PAI-1 promoter, suggesting that other promoter elements are involved in these responses. These mutations significantly reduced the -3.4kbp PAI-1 promoter response to serum. We concluded that ERalpha and ERbeta exert differential effects on the PAI-1 promoter activity in transfected BAECs. ERalpha activated the PAI-1 promoter through a proximal ERE (-427) and possibly additional EREs located within the PAI-1 promoter, whereas ERbeta suppressed the promoter construct via an unidentified mechanism. This is the first demonstration of the differential regulation of a vascular gene promoter by ERalpha and ERbeta.

Animals↗
PubMed1995

The effects of cycloheximide and WR-1065 on radiation-induced repair processes: a mechanism for chemoprevention.

The effects of cycloheximide (CHX) and 2-[(aminopropyl)-amino]ethanethiol (WR-1065), each alone or in combination, on radiation-induced mutation induction at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus and cell killing were investigated using a Chinese hamster ovary (CHO) AA8 cell system. Treatment with CHX, a potent inhibitor of protein synthesis, at a concentration of 10 micrograms/ml administered 30 min prior to irradiation with 7.5 Gy had no effect on cell survival but did reduce the radiation-induced mutation frequency (per 10(6) survivors) from 106.5 +/- 8.8 (SEM) to 36.2 +/- 5.6 (SEM). Exposure of cells to 4 mM WR-1065 reduced the mutation frequency to 44.8 +/- 4.2 (SEM), but the combination of agents afforded no additional protection, that is 41.1 +/- 3.3 (SEM). The mechanism of action attributed to CHX in reducing mutation frequency is its ability to prevent the induction of an error-prone repair system. Split-dose radiation experiments, that is 8 Gy versus 4 Gy + 4 Gy separated by 3 h, were performed to evaluate and contrast the relative abilities of CHX and WR-1065, each alone or in combination, in affecting cell survival. Cycloheximide administered to cells 30 min before the first radiation dose and present throughout the 3 h incubation time prior to the second dose inhibited split-dose repair as evidence by a reduction in surviving fraction by 60% as compared with the value obtained for non-CHX-treated cells that were exposed to two equal doses of 4 Gy. Cells exposed to 4 mM WR-1065 immediately following the first 4 Gy radiation dose and then washed free 2.5 h before exposure to a second Gy dose, which was also followed by a 30 min exposure to WR-1065, increased the surviving fraction by 80% over the value obtained for cells not exposed to WR-1065 during their split-dose radiation treatment. When CHX treatment was combined with WR-1065 was abolished, that is surviving cell fraction was again reduced by approximately 60% as compared with untreated control groups. These results indicate that protein synthesis is required for WR-1065 to affect split-dose related repair processes. Presumably, the inhibition of the induction of an error-phone repair system by CHX would account for its effects on both resultant decreases in mutation frequency and cell survival. In contrast, WR-1065 and/or its disulfide metabolite appear to facilitate the efficacy and fidelity of such a repair system once it is induced.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

A comparison of mutation rates for specific loci and chromosome regions in dysgenic hybrid males of Drosophila melanogaster.

The mutation rates of specific loci and chromosome regions were estimated for two types of dysgenic hybrid males. These came from crosses between P or Q males and M females in the P-M system of hybrid dysgenesis. The M X P hybrids were the more mutable for each of the loci and chromosome regions tested. The Beadex locus was highly mutable in these hybrids but did not mutate at all in the sample of gametes from the M X Q hybrids. The singed locus had 75% of the mutability of Beadex in the M X P hybrids; it was also mutable in the M X Q hybrids. The white locus was only slightly mutable in the M X P hybrids and not at all mutable in the M X Q hybrids. The mutations in singed and white probably arose from the insertion of P elements into these loci; the mutations at Beadex probably involved the action of a P element located near this locus on the X chromosome of the P strain that was used in the experiments. Mutations in two chromosome regions, one including the zeste-white loci and the other near the miniature locus, were much more frequent in the M X P hybrids than in the M X Q hybrids. These mutations also probably arose from P element insertions. The implication is that insertion mutations occur infrequently in the M X Q hybrids, possibly because most of the P elements they carry are defective. In M X P hybrids, there is variation among loci with respect to P element mutagenesis, indicating that P elements possess a degree of insertional specificity.

Animals↗
PubMed2003

Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia.

HESX1 is a paired-like homeodomain transcription factor that functions as a repressor of PROP1-mediated gene stimulation. Mutations in HESX1 have been implicated in cases of septooptic dysplasia and congenital hypopituitarism. All mutations in HESX1 identified to date have resulted in impaired DNA binding and defective HESX1 action. We have identified a novel HESX1 mutation in genomic nucleotide position 1684 (g.1684delG), which results in a mutant protein with increased DNA binding. In turn, this mutation causes increased repression of PROP1-dependent gene activity. These data suggest that enhancement of transcriptional repression during pituitary organogenesis is a novel mechanism for the development of congenital pituitary disorders.

Basic Helix-Loop-Helix Proteins↗
PubMed2001

Androgens, androgen receptors, and male gender role behavior.

Studies of genetic males with single gene mutations that impair testosterone formation or action and consequently prevent development of the normal male phenotype provide unique insight into the control of gender role behavior. 46,XY individuals with either of two autosomal recessive mutations [17 beta-hydroxysteroid dehydrogenase 3 (17 beta-HSD3) deficiency or steroid 5 alpha-reductase 2 (5 alpha-R2) deficiency] have a female phenotype at birth and are raised as females but frequently change gender role behavior to male after the expected time of puberty. In contrast, genetic males with mutations that impair profoundly the function of the androgen receptor are also raised as females and have consistent female behavior as adults. Furthermore, the rare men with mutations that impair estrogen synthesis or the estrogen receptor have male gender role behavior. These findings indicate that androgens are important determinants of gender role behavior (and probably of gender identity) and that this action is mediated by the androgen receptor and not the result of conversion of androgen to estrogen. The fact that all genetic males with 17 beta-HSD3 or 5 alpha-R2 deficiency do not change gender role behavior indicates that other factors are also important determinants of this process.

Androgens↗
PubMed1975

[A cytogenetic analysis of the antimutagenic action of alpha-tocopherol on spontaneous and radiation-induced chromosomal mutations].

The antimutagenic effect of alpha-tocopherol at concentrations of 1-10(-5)-1-10 mcC/ml was studied with respect to spontaneous and radiation-induced chromosome mutations in Allium fistulosum L. and Vicia faba L. It is established that at these concentrations alpha-tocopherol exhibits a significant antimutagenic activity, decreasing the frequency of chromosome mutations more than by 40-50%. No changes resulting from the antimutagenic effect of alpha-tocopherol were observed in the spectrum of structual mutations of chromosomes.

Chromosome Aberrations↗
PubMed1993

Mutation in a conserved motif next to the insulin receptor key autophosphorylation sites de-regulates kinase activity and impairs insulin action.

We have recently reported two non-insulin-dependent diabetic patients exhibiting a heterozygous point mutation (R1152-Q) next to the key tyrosine autophosphorylation sites (Y1146, Y1150, Y1151) of the insulin receptor. In the present study, we demonstrate that the Q1152 mutation alters a previously unrecognized consensus sequence in the insulin receptor family of tyrosine kinases. To define the effect of this alteration on insulin receptor function, the mutant insulin receptor (Q1152) was constructed and overexpressed in NIH-3T3 cells. In spite of normal insulin binding, "in vivo" and "in vitro" autophosphorylation as well as transphosphorylation by the wild-type receptor (WT) were deficient in Q1152 as compared with the transfected WT receptors. Insulin-stimulated kinase activity toward poly(Glu, Tyr) 4:1 and the endogenous substrates p120 and p175 were also impaired in Q1152. However, insulin-independent kinase activity of Q1152 was 2-5-fold higher than that of WT. While insulin stimulated 2-deoxyglucose uptake and glycogen synthase activity in WT-transfected cells with a sensitivity proportional to receptor number, no insulin stimulation was observed in Q1152 cells. Similar to the kinase, insulin-independent glycogen synthase activity and 2-deoxyglucose uptake were 2-fold higher in Q1152 than in either WT or parental cells. We conclude that the Q1152 mutation deregulates insulin receptor kinase and generates insulin insensitivity in cells. Alterations in this highly conserved region of the insulin receptor may contribute to non-insulin dependent diabetes mellitin pathogenesis in humans.

3T3 Cells↗
PubMed1996

Identification of natural monomeric response elements of the nuclear receptor RZR/ROR. They also bind COUP-TF homodimers.

The receptor RZR/ROR is an important member of the nuclear receptor superfamily and has recently been shown to be the nuclear receptor for the pineal gland hormone melatonin. RZR/ROR binds as a monomer to DNA, and the human 5-lipoxygenase gene has been identified as the first RZR/ROR/melatonin-responding gene. Another prominent nuclear receptor is COUP-TF, which binds as a dimer to DNA. In this study, the sequences of known promoter regions of genes that may be involved in the physiological action of melatonin have been screened for putative monomeric RZR/ROR response elements. The binding of RZR/ROR and COUP-TF was compared and quantified on a set of 12 putative response elements. Interestingly, COUP-TF homodimers were found to bind with high affinity to some of the monomeric RZR/ROR response elements. Four RZR/ROR response elements, found in the genes of the mouse bifunctional enzyme, the rat bone sialoprotein, mouse Purkinje cell protein 2, and human p21(WAF1/CIP1), were shown to be inducible by melatonin under conditions of low constitutive activity. Surprisingly, the constitutive activity of COUP-TF was also stimulated by an unknown serum compound. The novel Purkinje cell protein 2 and p21(WAF1/CIP1) RZR/ROR/melatonin-responding genes may be the key for understanding the role of RZR/RORalpha in the mouse mutation staggerer and the antiproliferative action of melatonin, respectively.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2005

Cell cycle-dependent dynamics and regulation of mitotic kinesins in Drosophila S2 cells.

Constructing a mitotic spindle requires the coordinated actions of several kinesin motor proteins. Here, we have visualized the dynamics of five green fluorescent protein (GFP)-tagged mitotic kinesins (class 5, 6, 8, 13, and 14) in live Drosophila Schneider cell line (S2), after first demonstrating that the GFP-tag does not interfere with the mitotic functions of these kinesins using an RNA interference (RNAi)-based rescue strategy. Class 8 (Klp67A) and class 14 (Ncd) kinesin are sequestered in an active form in the nucleus during interphase and engage their microtubule targets upon nuclear envelope breakdown (NEB). Relocalization of Klp67A to the cytoplasm using a nuclear export signal resulted in the disassembly of the interphase microtubule array, providing support for the hypothesis that this kinesin class possesses microtubule-destabilizing activity. The interactions of Kinesin-5 (Klp61F) and -6 (Pavarotti) with microtubules, on the other hand, are activated and inactivated by Cdc2 phosphorylation, respectively, as shown by examining localization after mutating Cdc2 consensus sites. The actions of microtubule-destabilizing kinesins (class 8 and 13 [Klp10A]) seem to be controlled by cell cycle-dependent changes in their localizations. Klp10A, concentrated on microtubule plus ends in interphase and prophase, relocalizes to centromeres and spindle poles upon NEB and remains at these sites throughout anaphase. Consistent with this localization, RNAi analysis showed that this kinesin contributes to chromosome-to-pole movement during anaphase A. Klp67A also becomes kinetochore associated upon NEB, but the majority of the population relocalizes to the central spindle by the timing of anaphase A onset, consistent with our RNAi result showing no effect of depleting this motor on anaphase A. These results reveal a diverse spectrum of regulatory mechanisms for controlling the localization and function of five mitotic kinesins at different stages of the cell cycle.

Active Transport, Cell Nucleus↗
PubMed1998

How organisms do the right thing: The attractor hypothesis.

Neo-Darwinian theory is highly successful at explaining the emergence of adaptive traits over successive generations. However, there are reasons to doubt its efficacy in explaining the observed, impressively detailed adaptive responses of organisms to day-to-day changes in their surroundings. Also, the theory lacks a clear mechanism to account for both plasticity and canalization. In effect, there is a growing sentiment that the neo-Darwinian paradigm is incomplete, that something more than genetic structure, mutation, genetic drift, and the action of natural selection is required to explain organismal behavior. In this paper we extend the view of organisms as complex self-organizing entities by arguing that basic physical laws, coupled with the acquisitive nature of organisms, makes adaptation all but tautological. That is, much adaptation is an unavoidable emergent property of organisms' complexity and, to some a significant degree, occurs quite independently of genomic changes wrought by natural selection. For reasons that will become obvious, we refer to this assertion as the attractor hypothesis. The arguments also clarify the concept of "adaptation." Adaptation across generations, by natural selection, equates to the (game theoretic) maximization of fitness (the success with which one individual produces more individuals), while self-organizing based adaptation, within generations, equates to energetic efficiency and the matching of intake and biosynthesis to need. Finally, we discuss implications of the attractor hypothesis for a wide variety of genetical and physiological phenomena, including genetic architecture, directed mutation, genetic imprinting, paramutation, hormesis, plasticity, optimality theory, genotype-phenotype linkage and puncuated equilibrium, and present suggestions for tests of the hypothesis. (c) 1998 American Institute of Physics.

Journal Article↗
PubMed2003

Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project.

BACKGROUND: Homozygotes for the thermolabile mutation (TT genotype) of the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) enzyme have elevated plasma concentrations of the cardiovascular disease risk factor homocysteine, particularly if folate depleted. OBJECTIVE: We examined the relations between thermolabile MTHFR, plasma homocysteine, plasma folate, and vascular disease risk. DESIGN: This was a case-control comparison in 711 vascular disease cases and 747 controls from 9 European countries. RESULTS: The TT genotype was associated with higher homocysteine and lower plasma folate than the CC and CT genotypes in both cases and controls and a nonsignificant increase in vascular disease risk (1.26; 95% CI: 0.88, 1.81; P = 0.20). The frequency of the TT genotype in cases was not significantly different from that in controls (12.8% compared with 10.8%). After adjustment for traditional risk factors, the TT genotype was associated with an odds ratio of 1.48 (1.0, 2.20) for risk of vascular disease. This risk was attenuated after further adjustment for homocysteine. In subgroups with homocysteine concentrations >or= 9 micro mol/L, risk tended to be higher in CC than in TT subjects. However, CC subjects were characterized by a higher prevalence of the conventional risk factors associated with both elevated plasma homocysteine and serum creatinine. After adjustment, the risk of vascular disease associated with each genotype was not significantly different. CONCLUSIONS: There was a strong graded association between homocysteine and vascular risk in all genotypes. MTHFR genotype is a key determinant of plasma total homocysteine concentrations. The initially nonsignificant risk estimate associated with the TT genotype was strengthened after adjustment for conventional cardiovascular disease risk factors but was attenuated after adjustment for plasma folate and total homocysteine. The modest risk increase conferred by the TT genotype is mediated mainly by increased total homocysteine and low plasma folate concentrations.

Adult↗
PubMed1984

Effect of norharman on DNA strand breaks and mutation of Chinese hamster V79 cells by chemical carcinogens.

The effect of norharman, which shows a comutagenic activity in the Salmonella mutation assay, was examined on the action of mutagens towards Chinese hamster V79 cells. Norharman reduced the DNA strand breaks by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), but enhanced the 4-hydroxyaminoquinoline l-oxide ( 4HAQO )-induced DNA strand breaks. Norharman also reduced the cytotoxicity and the mutagenicity of MNNG but enhanced the cytotoxicity of 4HAQO to V79 cells. In the Salmonella mutation assay, norharman showed no effect on the mutagenic activity of MNNG but reduced the mutagenic activity of 4HAQO . The effect of norharman on the action of mutagens to V79 cells appeared dependent on mutagens and did not correlate with the effect observed in Salmonella mutation assay.

4-Hydroxyaminoquinoline-1-oxide↗
PubMed2002

[Novel mode of action of ribavirin (Rebetol), a drug for the treatment of chronic hepatitis C: inducting the mutation of RNA viruses].

Ribavirin (Rebetol) is an antiviral agent used in combination with interferon alpha-2b (IFN alpha-2b) for the treatment of chronic hepatitis C. Ribavirin has been reported to have a broad-spectrum antiviral activity mainly against RNA viruses. The effect of ribavirin was potentiated when administered in combination with IFN alpha-2b in an antiviral assay using bovine viral diarrhea virus as a surrogate for hepatitis C virus (HCV). Inhibition of host inosine monophosphate dehydrogenase and inhibition of RNA-dependent RNA polymerase (RdRp) of RNA viruses have been reported as the modes of action of ribavirin. Recently, ribavirin has been shown to induce mutation as template for newly generated RNA after uptake in RNA by RdRp of poliovirus, which is an RNA virus as in the case of HCV. It has also been shown that the infectivity of viruses is drastically reduced by the very slight increase in mutations induced by ribavirin. This effect as a mutagen on RNA viruses is a novel mode of ribavirin, and it is thought necessary to classify ribavirin into a new antiviral drug class.

Animals↗
PubMed2006

Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms.

The revertant mutations G550E and 4RK [the simultaneous mutation of four arginine-framed tripeptides (AFTs): R29K, R516K, R555K, and R766K] rescue the cell surface expression and function of F508del-cystic fibrosis (CF) transmembrane conductance regulator (-CFTR), the most common CF mutation. Here, we investigate their mechanism of action by using biochemical and functional assays to examine their effects on F508del and three CF mutations (R560T, A561E, and V562I) located within a conserved region of the first nucleotide-binding domain (NBD1) of CFTR. Like F508del, R560T and A561E disrupt CFTR trafficking. G550E rescued the trafficking defect of A561E but not that of R560T. Of note, the processing and function of V562I were equivalent to that of wild-type (wt)-CFTR, suggesting that V562I is not a disease-causing mutation. Biochemical studies revealed that 4RK generates higher steady-state levels of mature CFTR (band C) for wt- and V562I-CFTR than does G550E. Moreover, functional studies showed that the revertants rescue the gating defect of F508del-CFTR with different efficacies. 4RK modestly increased F508del-CFTR activity by prolonging channel openings, whereas G550E restored F508del-CFTR activity to wt levels by altering the duration of channel openings and closings. Thus, our data suggest that the revertants G550E and 4RK might rescue F508del-CFTR by distinct mechanisms. G550E likely alters the conformation of NBD1, whereas 4RK allows F508del-CFTR to escape endoplasmic reticulum retention/retrieval mediated by AFTs. We propose that AFTs might constitute a checkpoint for endoplasmic reticulum quality control.

Animals↗
PubMed1983

Alternative hypotheses for the role of promotion in chemical carcinogenesis.

A new protocol for carcinogenesis in rat liver is described in order that confirmatory experiments might be undertaken concurrently. The basic protocol, designated IPI (initiator + promoter + initiator), is presented in several alternative forms, including the possible use of X-irradiation as the initiator. The rationale is discussed in terms of the two-hit somatic mutation theory of Armitage and Doll, with an initial hit produced by the first dose of initiator and expansion of single cells to sizable clones by promotion thereby increasing the probability of a second hit by the second dose of initiator. The question of relevant mutations was taken up and it was proposed that genes for chalones (C) and for chalone receptors (R) are logical targets for consideration in a two-mutation sequence. Alternative hypotheses pertaining to promoter action were described in terms of possible mechanisms by which nonelectrophilic promoters might simulate a second mutation by increasing or decreasing the levels of a nonchromosomal replicating particle in target cells.

Animals↗