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PubMed2005

The epigenetics of oral cancer.

Whilst genetic alterations in oral cancer have long been documented, the appreciation of epigenetic changes is more recent. Epigenetic changes alter expression of tumour suppressor genes without changes in DNA sequence. Epigenetic mechanisms such as DNA methylation, histone methylation and deacetylation have been shown to silence key genes involved in cell proliferation, differentiation and genome integrity, and clearly have a central role in oral cancer. The pattern of hypermethylation in any individual tumour can now be accurately determined, which may find application in molecular staging. In addition, current trials are evaluating the safety and efficacy of agents affecting epigenetic changes in cancer patients which hold some therapeutic promise.

Acetylation↗

PubMed2002

Strain and process development for the production of human cytokines in Hansenula polymorpha.

The early status of strain development for the production of interleukin (IL)-6, IL-8, IL-10, and interferon (IFN) gamma is described. The general approach to generating such strains was to amplify gene sequences encoding the mature forms of the various cytokines by PCR from commercially available cDNA sources. The design of the amplificates allowed an in-frame fusion to an MFalpha1 leader segment contained in two basic expression vectors, pFPMT121-MFalpha1 and pTPSMT-MFalpha1. The two vectors differ in that one harbors the methanol-inducible FMD promoter and the other the constitutive TPS1 promoter as control elements for heterologous gene expression. The most advanced process development example is that of IFNalpha-2a. Here, the MOX promoter derived from another key gene of methanol metabolism is used for expression control. The successful development of a production process for Hansenula polymorpha-derived IFNalpha-2a is summarized. This was achieved by combining genetic engineering of suitable production strains with improved processing capabilities for the secreted cytokine, and by purification procedures from cultures grown in yeast extract-peptone-glycerol-based media.

Amino Acid Sequence↗

PubMed2001

Convergence of two global transcriptional regulators on nitrogen induction of the stress-acclimation gene nblA in the cyanobacterium Synechococcus sp. PCC 7942.

Cyanobacteria respond to environmental stress conditions by degrading their phycobilisomes, the light harvesting complexes for photosynthesis. The expression of nblA, a key gene in this process, is controlled by the response regulator NblR in Synechococcus sp. PCC 7942. Here we show that, under nitrogen stress, nblA is also regulated by NtcA, the global regulator for nitrogen control. NtcA activation of nblA was found to be nitrogen-specific and did not take place under sulphur stress. Transcripts from the two major transcription start points (tsp) for the nblA gene were induced in response to nitrogen and sulphur starvation. The most active one (tspII) required both NblR and NtcA to induce full nblA expression under nitrogen starvation. NblR and NtcA bound in vitro to a DNA fragment from the nblA promoter region, suggesting that, under nitrogen stress, both NblR and NtcA activate the main regulated promoter (PnblA-2) by direct DNA-binding. The structure of PnblA-2 differs from that of the canonical NtcA-activated promoter and it is therefore proposed to represent a novel type of NtcA-dependent promoter. We analysed expression patterns from ntcA and selected NtcA targets in NtcA(-), NblR(-) and wild-type strains, and discuss data suggesting further interrelations between phycobilisome degradation and nitrogen assimilation regulatory pathways.

Bacterial Proteins↗

PubMed2006

Transcriptomic analysis of extensive changes in metabolic regulation in Kluyveromyces lactis strains.

Genome-wide analysis of transcriptional regulation is generally carried out on well-characterized reference laboratory strains; hence, the characteristics of industrial isolates are therefore overlooked. In a previous study on the major cheese yeast Kluyveromyces lactis, we have shown that the reference strain and an industrial strain used in cheese making display a differential gene expression when grown on a single carbon source. Here, we have used more controlled conditions, i.e., growth in a fermentor with pH and oxygen maintained constant, to study how these two isolates grown in glucose reacted to an addition of lactose. The observed differences between sugar consumption and the production of various metabolites, ethanol, acetate, and glycerol, correlated with the response were monitored by the analysis of the expression of 482 genes. Extensive differences in gene expression between the strains were revealed in sugar transport, glucose repression, ethanol metabolism, and amino acid import. These differences were partly due to repression by glucose and another, yet-unknown regulation mechanism. Our results bring to light a new type of K. lactis strain with respect to hexose transport gene content and repression by glucose. We found that a combination of point mutations and variation in gene regulation generates a biodiversity within the K. lactis species that was not anticipated. In contrast to S. cerevisiae, in which there is a massive increase in the number of sugar transporter and fermentation genes, in K. lactis, interstrain diversity in adaptation to a changing environment is based on small changes at the level of key genes and cell growth control.

Acetates↗

PubMed2004

Peroxisome proliferator-activated receptor delta activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes.

Peroxisome proliferator-activated receptors (PPARalpha, -gamma and -delta) are nuclear receptors involved in transcriptional regulations of lipid metabolism. The effect of PPARalpha in regulation of cardiac fatty acid oxidation has been well characterized. Whether PPARdelta also independently regulates fatty acid oxidation in the heart remains unclear. In this study, we tested the hypothesis that PPARdelta activates fatty acids oxidation in cardiomyocytes through transcriptional activation that are independent of PPARalpha. Our results first indicate that PPARdelta abundantly expresses in nucleus of cardiomyocytes. Palmitate oxidation rates were significantly increased in both neonatal and adult cardiomyocytes after treatment of a PPARdelta-selective ligand (GW0742). Further increases of fatty acid oxidation were evident when the treatment was applied to cardiomyocytes overexpressing a wild type PPARdelta, but not a mutant PPARdelta that lacks the intact carboxyl ligand-binding domain. Furthermore, genes of fatty acid oxidation enzymes were significantly upregulated in cultured rat neonatal cardiomyocytes when exposed to GW0742. GW0742 can restore partly the expression of certain key genes of fatty acid oxidation in mouse adult cardiomyocytes isolated from PPARalpha knockout mice. Therefore, while active crosstalk between PPARdelta and -alpha may exist, PPARdelta regulates cardiac fatty acid oxidation in the heart at least partly independent of PPARalpha. We conclude that PPARdelta may play a key role in cardiac energy balance and may serve as a "sensor" of fatty acid of other endogenous ligands in controlling fatty acids oxidation levels in the hearts under normal and pathological conditions.

Animals↗

PubMed1992

New gene in the homologous human 11q13-q14 and mouse 7F chromosomal regions.

Alterations in the chromosomal region 11q13-11q14 are involved in several pathologies in which most of the key genes remain to be identified. In an effort to isolate as many candidates as possible, we are cloning genes from this region. We report here the mapping of a new sequence from 11q13.5-11q14. This sequence, designated D11S833E, putatively encodes a new gene, provisionally named GARP. We cloned its homologous sequence in the mouse and located it on Chromosome (Chr) 7, region F. The human and mouse genes belong to a conserved group of synteny. This, together with the similar conservation of the FGF and TYR genes, indicates that the human 11q13-q14 and mouse 7E-7F regions share homology.

Animals↗

PubMed1994

Roles of the GLABROUS1 and TRANSPARENT TESTA GLABRA Genes in Arabidopsis Trichome Development.

Arabidopsis trichomes are branched, single-celled epidermal hairs. These specialized cells provide a convenient model for investigating the specification of cell fate in plants. Two key genes regulating the initiation of trichome development are GLABROUS1 (GL1) and TRANSPARENT TESTA GLABRA (TTG). GL1 is a member of the myb gene family. The maize R gene, which can functionally complement the Arabidopsis ttg mutation, encodes a basic helix-loop-helix protein. We used constitutively expressed copies of the GL1 and R genes to test hypotheses about the roles of GL1 and TTG in trichome development. The results support the hypothesis that TTG and GL1 cooperate at the same point in the trichome developmental pathway. Furthermore, the constitutive expression of both GL1 and R in the same plant caused trichomes to develop on all shoot epidermal surfaces. Results were also obtained indicating that TTG plays an additional role in inhibiting neighboring cells from becoming trichomes.

Journal Article↗

PubMed2002

Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1.

The 11p15 mucin genes (MUC2, MUC5AC, MUC5B and MUC6) possess a cell-specific pattern of expression in normal lung that is altered during carcinogenesis. Growth factors of the epidermal growth factor family are known to target key genes that in turn may affect the homeostasis of lung mucosae. Our aim was to study the regulation of the 11p15 mucin genes both at the promoter and protein levels to assess whether their altered expression may represent a key event during lung carcinogenesis. Studies were performed in the mucoepidermoid NCI-H292 lung cancer cell line. Cell treatment with epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), or tumor necrosis factor alpha (TNF-alpha) resulted in a dramatic increase of MUC2 and MUC5AC mRNAs levels, promoter activity, and apomucin expression, whereas those of MUC5B and MUC6 were unchanged. pGL3 deletion mutants of MUC2, MUC5AC, and MUC5B promoters were constructed and used in transient transfection assays to characterize EGF- and TGF-alpha-responsive regulatory regions within the promoters. They were located in the -2627/-2097 and -202/-1 regions of MUC2 and MUC5AC promoters, respectively. Finally, we demonstrate that transcription factor Sp1 not only binds and activates MUC2 and MUC5AC promoters but also participates to their EGF- and TGF-alpha-mediated up-regulation. We also show that Sp3 is a strong inhibitor of 11p15 mucin gene transcription. In conclusion, MUC2 and MUC5AC are two target genes of EGFR ligands in lung cancer cells, and up-regulation of these two genes goes through concomitant activation of the EGFR/Ras/Raf/Extracellular Signal-regulated Kinase-signaling pathway and Sp1 binding to their promoters.

Base Sequence↗

PubMed2000

Krüppel-homolog, a stage-specific modulator of the prepupal ecdysone response, is essential for Drosophila metamorphosis.

We have characterised a P-element-induced prepupal mutant of Drosophila melanogaster which after an apparently normal embryonic and larval development fails to complete head eversion, an essential step in metamorphosis. The P-element insertion disrupts an ecdysone-regulated transcript which, although expressed during embryonic and larval stages, appears critical for preparing the late prepupal response to ecdysone. By a combination of molecular and genetic studies, in which we recovered new alleles, we show that the locus is complex, containing at least two distinct promoters. Its transcripts contain a short region described previously by R. Schüh et al. (1986, Cell 47, 1025-1032), who screened for homologues of the Krüppel gene. Our studies on the corresponding gene, named Krüppel-homolog (Kr-h), add to a growing body of evidence that specific isoforms of a number of key genes are implicated in both embryogenesis and metamorphosis.

Amino Acid Sequence↗

PubMed2001

The effects of aging on gene expression in the hypothalamus and cortex of mice.

A better understanding of the molecular effects of aging in the brain may help to reveal important aspects of organismal aging, as well as processes that lead to age-related brain dysfunction. In this study, we have examined differences in gene expression in the hypothalamus and cortex of young and aged mice by using high-density oligonucleotide arrays. A number of key genes involved in neuronal structure and signaling are differentially expressed in both the aged hypothalamus and cortex, including synaptotagmin I, cAMP-dependent protein kinase C beta, apolipoprotein E, protein phosphatase 2A, and prostaglandin D. Misregulation of these proteins may contribute to age-related memory deficits and neurodegenerative diseases. In addition, many proteases that play essential roles in regulating neuropeptide metabolism, amyloid precursor protein processing, and neuronal apoptosis are up-regulated in the aged brain and likely contribute significantly to brain aging. Finally, a subset of these genes whose expression is affected by aging are oppositely affected by exposure of mice to an enriched environment, suggesting that these genes may play important roles in learning and memory.

Aging↗

PubMedDate not supplied

Genetic predictors of cardiovascular disease: the use of chip technology.

Cardiovascular disease, a primary cause of mortality in the United States, has a complex pathologic process involving many genes. The high-throughput technology (microarray or "DNA chip") used to decipher the human genome is now being employed to identify key genes in its development. A study focusing on candidate genes associated with premature cardiovascular disease discovered that missense variations in the thrombospondin 1 and 4 genes were associated with premature coronary artery disease, while a mutation in the non-coding region of a thrombospondin 2 gene imparts protection from developing heart disease. Although the clinical implications of microarray technology are still under investigation, this research may lead to a diagnostic test to determine a patient's risk for developing heart disease.

Cardiovascular Diseases↗

PubMed1988

Genetics of the black-tailed red plumage pattern in Villafranquina chickens.

Data are presented on the genetics of the plumage color of the Villafranquina, a breed of Spanish chicken representing a black-tailed red type of the columbian restriction pattern. Crosses between Villafranquina females, which show a large amount of secondary pattern, and Brown and Buttercup tester males suggested that this breed carries the brown allele (eb) at the E-locus. This allele is modified by the dark-brown columbian-like gene (Db), resulting in the plumage pattern characteristic of the breed. The degree of expression of Db varies markedly depending on other key genes present. This gene acted as an incomplete dominant when crossed to brown (eb) and buttercup (ebc) tester lines. However, in the presence of the birchen (ER) gene, Db was recessive in females but dominant in males, suggesting sex-influenced inheritance. Silver (S) does not alter the brown down of Db-modified ER, although it does express itself readily on a brown (eb) background. Variability in the expression of Db in both F1 and F2 populations suggests that it sometimes interacts with not yet identified modifying genes.

Animals↗

PubMed1993

Prenatal ontogeny of tyrosine hydroxylase gene expression in the rat ventral mesencephalon.

We have examined the development of dopaminergic (DA) neurons in the embryonic mesencephalon with regard to the expression of the gene coding for tyrosine hydroxylase (TH). Mesencephalic DA neurons from rat embryos aged E13 to E21 were analyzed using a quantitative in situ hybridization protocol featuring a 35S-labeled RNA probe complimentary to TH mRNA. In the early-to-mid stage embryonic brains, the expression of the TH gene was examined relative to the position of individual, migrating DA cells in the caudal-rostral and dorsal-ventral axes of the mesencephalon. In the later embryonic subjects, neurons were analyzed according to their position in one of the midbrain DA nuclei. The ontogeny of TH gene expression in the rat mesencephalon exhibited two phases: during the early phase (E13-E15), we observed major fluctuations in the level of TH gene expression accompanying the differentiation and maturation processes of the DA cells. Later, in the mid-to-late gestation fetus (E18-E21), TH gene expression generally stabilized as TH mRNA-expressing neurons reached their final anatomical positions within the mesencephalic DA complex. Our data demonstrate the complex dynamics which characterize the ontogeny of TH gene expression in the prenatally developing mesencephalon, and suggest a connection between the maturational level of DA neurons and the expression of the key gene regulating their principle neurotransmitter.

Animals↗

PubMed2002

Analysis of the genetic potential and gene expression of microbial communities involved in the in situ bioremediation of uranium and harvesting electrical energy from organic matter.

The proposed research will investigate two microbial communities that are of direct relevance to Department of Energy interests. One is the microbial community associated with the in situ bioremediation of uranium-contaminated groundwater. The second is a microbial community that harvests energy from waste organic matter in the form of electricity. These studies will address DOE needs for (1) remediation of metals and radionuclides at DOE sites and (2) the development of cleaner forms of energy and biomass conversion to energy. Our previous studies have demonstrated that the microbial communities involved in uranium bioremediation and energy harvesting are both dominated by microorganisms in the family Geobacteraceae and that the organisms in this family are responsible for uranium bioremediation and electron transfer to electrodes. The initial objectives of this study are to (1) describe the genetic potential of the Geobacteraceae that predominate in the environments of interest; (2) identify conserved patterns of gene expression within the Geobacteraceae family in response to a range of environmental conditions; (3) begin to identify mechanisms controlling the expression of key genes related to survival, growth, and activity in subsurface environments and on electrodes; and (4) use the results from subobjectives 1-3 to develop a conceptual model for predicting gene expression of Geobacteraceae in the environments of interest. This will serve as the basis for a subsequent simulation model of the growth and activity of Geobacteraceae in the subsurface and on electrodes.

Biodegradation, Environmental↗

PubMed2006

N-ethyl-N-nitrosourea (ENU) mutagenesis and male fertility research.

Male infertility affects about 1 in 25 men in the western world. Conversely, there is an urgent requirement for additional male-based contraceptives, yet progress in both areas has been severely hampered by a lack of knowledge of the biochemistry and physiology of male reproductive function. It is only through a thorough knowledge of these processes that we can hope to insightfully regulate male reproductive function. Without doubt, mouse models will form an important foundation in any future process. In recent years, the chemical mutagen N-ethyl-N-nitrosourea (ENU) has been used widely to identify genes essential for a range of biological systems including male infertility. These studies have shown random mutagenesis is an attractive means of identifying key genes for male fertility. This technique has distinct, but complementary advantages compared to knockout technologies. Specifically, it allows the removal of researcher bias whereby only pre-conceived genes are tested for function; it produces mice with a guaranteed phenotype and allows for the production of allelic series of mice to dissect all aspects of gene function. ENU mouse mutagenesis programs will enable advances in the diagnosis and treatment of human male infertility and ultimately aid in the development of novel male-based contraceptives.

Alkylating Agents↗

PubMed2006

Isolation of the Atlantic salmon tyrosinase gene family reveals heterogenous transcripts in a leukocyte cell line.

In ectothermic vertebrates, visceral organs harbor melanin-containing cells. Their ability as pigment producers is nevertheless disputed. To address expression of the key genes for melanogenesis in Atlantic salmon (Salmo salar), a tyrosinase-positive leukocyte cell line (SHK-1) and skin were used to obtain full-length tyrosinase (Tyr), tyrosinase-like protein-1 (Tyrp1), and dopachrome tautomerase (Dct) mRNA transcripts. In the SHK-1 cells, two different Tyrp1 transcripts were identified, one lacking exon 1. However, only the full-length version of Tyrp1 was identified in the skin. Sequencing of Tyrp1 genomic region revealed that the two Tyrp1 transcripts might originate from two different loci, possibly a result of pseudo-tetraploidity of the Atlantic salmon genome. Expression of Tyr, Tyrp1 and Dct was investigated by quantitative real-time reverse transcriptase polymerase cain reaction showing highest expression in the SHK-1 cell line and skin, intermediate in pronephros, and negligible or absent in liver and muscle. Histological approaches were used to demonstrate melanin and revealed presence of melanized cells in skin, kidney and liver, and absence of such cells in muscle. In addition to verify melanin synthesis abilities of visceral-located cells, our results indicate loci-specific transcription differences between populations of melanin-producing cells in Atlantic salmon.

Amino Acid Sequence↗

PubMed1992

Why we have (only) five fingers per hand: hox genes and the evolution of paired limbs.

Limb development has long been a model system for studying vertebrate pattern formation. The advent of molecular biology has allowed the identification of some of the key genes that regulate limb morphogenesis. One important class of such genes are the homeobox-containing, or Hox genes. Understanding of the roles these genes play in development additionally provides insights into the evolution of limb pattern. Hox gene expression patterns divide the embryonic limb bud into five sectors along the anterior/posterior axis. The expression of specific Hox genes in each domain specifies the developmental fate of that region. Because there are only five distinct Hox-encoded domains across the limb bud there is a developmental constraint prohibiting the evolution of more than five different types of digits. The expression patterns of Hox genes in modern embryonic limb buds also gives clues to the shape of the ancestral fin field from which the limb evolved, hence elucidating the evolution of the tetrapod limb.

Animals↗

PubMed2005

pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective.

Genetic, physiological and pharmacological studies are gradually revealing the molecular basis of chloroquine resistance (CQR) in the malaria parasite, Plasmodium falciparum. Recent highlights include the discovery of a key gene associated with resistance, pfcrt (Plasmodium falciparum chloroquine resistance transporter; PfCRT), encoding a novel transporter, and the characterization of global selective sweeps of haplotypes containing a K76T amino acid change within this protein. Little is known about the cellular mechanism by which resistant parasites escape the effects of chloroquine (CQ), one of the most promising drugs ever deployed, due in part to an unresolved mechanism of action. The worldwide spread of CQR argues that investigations into these mechanisms are of little value. We propose, to the contrary, that the reconstruction of the evolutionary and molecular events underlying CQR is important at many levels, including: (i) its potential to assist in the development of rational approaches to thwart future drug resistances; (ii) the stimulation of the use of CQ-like compounds in drug combinations for new therapeutic approaches; and (iii) the consideration of how the CQ-selected genome will function as the context in which current and future drugs will act, particularly in light of the many reports of multidrug resistance. The purpose of this review is to highlight, discuss and in some cases challenge the interpretations of recent findings on CQR. We consider the natural function of the PfCRT protein, the role of multiple genes and "genetic background" in the CQR mechanism, and the evolution of CQR in parasite populations. Genetic transformation techniques are improving in P. falciparum and continue to provide important insight into CQR. Here, we also discuss more subtle, yet important pharmacological approaches that may have been overlooked in a traditional "gene for drug resistance" way of thinking.

Animals↗