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At least 685 records · Page 38Linked to original sources
PubMed2000

Genomic organization and gene function in Leishmania.

Sequencing of the Leishmania major Friedlin genome is well underway with chromosome 1 (Chr1) and Chr3 having been completely sequenced, and Chr4 virtually complete. Sequencing of several other chromosomes is in progress and the complete genome sequence may be available as soon as 2003. A large proportion ( approximately 70%) of the newly identified genes remains unclassified, with many of these being potentially Leishmania- (or kinetoplastid-) specific. Most interestingly, the genes are organized into large (>100-300 kb) polycistronic clusters of adjacent genes on the same DNA strand. Chr1 contains two such clusters organized in a 'divergent' manner, i. e. the mRNAs for the two sets of genes are both transcribed towards the telomeres. Chr3 contains two 'convergent' clusters, with a single 'divergent' gene at one telomere, with the two large clusters separated by a tRNA gene. We have characterized several genes from the LD1 (Leishmania DNA 1) region of Chr35. BT1 (formerly ORFG) encodes a biopterin transporter and ORFF encodes a nuclear protein of unknown function. Immunization of mice with recombinant antigens from these genes results in significant reduction in parasite burden following Leishmania challenge. Recombinant ORFF antigen shows promise as a serodiagnostic. We have also developed a tetracycline-regulated promoter system, which allows us to modulate gene expression in Leishmania.

Animals↗
PubMed1998

MLL, a mammalian trithorax-group gene, functions as a transcriptional maintenance factor in morphogenesis.

Determinative events in vertebrate embryogenesis appear to require the continuous expression of spatial regulators such as the clustered homeobox genes. The mechanisms that govern long-term patterns of gene expression are not well understood. In Drosophila, active and silent states of developmentally regulated loci are maintained by trithorax and Polycomb group. We have examined the developmental role of a mammalian homolog of trx and putative oncogene, Mll. Knockout mice reveal that Mll is required for maintenance of gene expression early in embryogenesis. Downstream targets of Mll including Hoxa7 are activated appropriately in the absence of Mll but require Mll for sustaining their expression. The Mll-/- phenotype manifests later in development and is characterized by branchial arch dysplasia and aberrant segmental boundaries of spinal ganglia and somites. Thus, Mll represents an essential mechanism of transcriptional maintenance in mammalian development, which functions in multiple morphogenetic processes.

Animals↗
PubMed2006

Differentiation stage-specific analysis of gene function with inducible short hair-pin RNA in differentiating embryonic stem cells.

Cell differentiation is regulated by spatial and temporal coordination of gene expressions. Previously, we have established an embryonic stem (ES) cell differentiation system that can trace early cardiovascular developmental process in vitro. Here we show that tetracycline-induced short hair-pin RNA (shRNA) expression in differentiating ES cells successfully suppressed stage-specific genes for differentiation and modified cell fates. We established ES cell lines carrying shRNA gene driven by tRNA(val) promoter with tetracycline operator sequences (tet-ON system). When expression of vascular endothelial growth factor receptor-2 (VEGFR2) gene, a vascular progenitor and mesoderm marker and an essential gene for endothelial cell (EC) differentiation, was suppressed by shRNA in early ES cell differentiation, appearance of VEGFR2(+) mesoderm cells was substantially reduced. Suppression of VEGFR2 expression at mesoderm stage almost completely inhibited EC differentiation from VEGFR2(+) mesoderm cells. This novel experimental system, thus, can selectively determine stage-specific roles of genes in differentiation in vitro.

Cell Differentiation↗
PubMed1990

Abnormalities of carbohydrate metabolism and of OCT gene function in the Rett syndrome.

The pathogenetic basis of the Rett syndrome (RS) is unknown: an X-linked dominant, male-lethal gene defect is thought likely. We present a girl with RS who has defects both of the urea cycle and of carbohydrate metabolism resulting in fasting hypoglycaemia, post-prandial hyperlactataemia and excess urinary orotic acid excretion after alanine load. Her sister has a similar clinical picture, but less marked metabolic anomalies. The mother of these sisters has abnormal urinary orotic acid excretion; she transmitted opposite ornithine carbomoyltransferase (OCT) alleles to the two girls. Another girl with RS has similar metabolic responses to fasting and to carbohydrate load. We conclude that RS may be an aetiologically homogeneous condition, but that it includes a variable pattern of metabolic anomalies, and that the gene defect is distinct from the OCT locus.

Adolescent↗
PubMed1987

Loss of expression of a differentiated function gene, steroid 17 alpha-hydroxylase, as adrenocortical cells senescence in culture.

Senescence in cultured adrenocortical cells involves changes in expression of differentiated functions as well as changes in responses to mitogenic stimulation. Steroid 17 alpha-hydroxylase (steroid 17 alpha-monooxygenase, EC 1.14.99.9) is an adrenal-specific enzyme, the expression of which is dependent on the presence of stimulators of cyclic AMP production, such as cholera toxin. Dot-blot hybridization of RNA from bovine adrenocortical cells that had been incubated with cholera toxin showed a marked decline in 17 alpha-hydroxylase mRNA levels as a function of population doubling level, closely paralleling the decline in induction of 17 alpha-hydroxylase enzyme activity. The lower levels of 17 alpha-hydroxylase induction did not result from a requirement for a longer time period for induction or from a specific defect in response to cholera toxin and were not caused by a general failure of enzyme induction in response to cyclic AMP. The decreased growth rate in older cells results from a general decline in response to several growth factors. However, the decline in 17 alpha-hydroxylase induction did not result from a loss of response of the cells to mitogens, since quiescent cells at a low population doubling level showed stimulation of 17 alpha-hydroxylase mRNA by cholera toxin to levels similar to those in nonquiescent cultures and added mitogens either had no effect on 17 alpha-hydroxylase mRNA levels or decreased them. There was, however, a specific posttranscriptional effect of insulin on 17 alpha-hydroxylase. The loss of 17 alpha-hydroxylase induction is unlikely to result from overgrowth of a minority cell type lacking the ability to induce 17 alpha-hydroxylase, because adrenocortical cell clones that had high levels of 17 alpha-hydroxylase induction gave rise to cells with lower levels of induction on subcloning. Thus, loss of 17 alpha-hydroxylase activity in adrenocortical cellular senescence results from a primary failure of accumulation of 17 alpha-hydroxylase mRNA after incubation with the inducing agent.

Adrenal Cortex↗
PubMed1997

Blood pressures and cardiovascular homeostasis in mice having reduced or absent angiotensin-converting enzyme gene function.

We studied cardiovascular phenotypes in wild-type (+/+), heterozygous (+/-), and homozygous mutant (-/-) mice for an insertional inactivation of the angiotensin-converting enzyme (ACE) gene (Ace in mice, ACE in humans). Compared with +/+ mice, baseline mean arterial pressure was not significantly altered in +/- mice but was reduced by 51+/-4 mm Hg in -/- mice. Although the pressor response to injected angiotensin II did not differ significantly in the three genotypic groups, the pressor response to angiotensin I was strongly affected by Ace genotype: Compared with the response in the +/+ group (+26% of baseline), the response to Ang I was close to half normal (+12%) in the +/- group and virtually abolished (+1%) in the -/- group. The depressor response to injected bradykinin was significantly enhanced in the +/- and -/- groups compared with the +/+ group. Ace expression and ACE activity were directly related to functional Ace copy number, and renin and angiotensinogen mRNA levels were inversely related to Ace copy number. Angiotensin type 1A receptor mRNA levels were not significantly different in the +/+, +/-, and -/- groups. We conclude that (1) ACE is essential for the maintenance of normal blood pressure; (2) subnormal levels of ACE affect the blood pressure responses to infused angiotensin I and bradykinin in vivo; and (3) compensations for inactivation of one Ace copy, which include increased expression of renin, normalize blood pressure in heterozygotes.

Analysis of Variance↗
PubMed2003

The 5' terminal oligopyrimidine tract of human elongation factor 1A-1 gene functions as a transcriptional initiator and produces a variable number of Us at the transcriptional level.

The human elongation factor 1A-1 (eEF1A-1) gene is a member of the 5' terminal oligopyrimidine tract (5' TOP) gene family, and the number of thymidines (Ts) at the 5' TOP of cDNAs corresponding to this gene is known to show variation. Here we determined the 5'-end sequences of 125 eEF1A-1 clones and the complete sequences of 19 eEF1A-1 clones from an oligo-capped cDNA library and showed that variation in the number of Ts is generated by an in vivo process, not by an in vitro artifact during the construction of the cDNA library. Moreover, using green fluorescent protein transgenic mice, we demonstrated that the variation in T number is probably generated during or after transcription. We also introduced various mutations in the mRNA start site of this gene, particularly in the T stretch at the 5' TOP, and examined the effects on the promoter activity. The results showed that at least three Ts must exist at the 5' TOP for the high transcriptional activity of the eEF1A-1 gene promoter. Many other housekeeping genes, including ribosomal protein genes, are also members of the 5' TOP gene family, and the 5' TOP sequence may be an important core-promoter element of these genes.

5' Untranslated Regions↗
PubMed2006

Regulation of microRNA by antagomirs: a new class of pharmacological antagonists for the specific regulation of gene function?

The discovery of small "noncoding" or "nonmessenger" RNA molecules that are repressors of translation (microRNAs) has provided the opportunity to specifically suppress a gene or clusters of genes. Moreover, the recent employment of synthetic analogs of these small RNA molecules termed "antagomirs" has shown that microRNAs of interest can be specifically targeted. Understanding the role of microRNAs in fundamental processes associated with complex diseases such as asthma, chronic obstructive pulmonary disease, cancer, chronic infections, and immune disorders may aid in disease diagnosis and prognosis and potentially identify new therapeutic targets.

Gene Expression Regulation↗
PubMed2004

The ULTRAPETALA1 gene functions early in Arabidopsis development to restrict shoot apical meristem activity and acts through WUSCHEL to regulate floral meristem determinacy.

Shoot and floral meristem activity in higher plants is controlled by complex signaling networks consisting of positive and negative regulators. The Arabidopsis ULTRAPETALA1 (ULT1) gene has been shown to act as a negative regulator of meristem cell accumulation in inflorescence and floral meristems, as loss-of-function ult1 mutations cause inflorescence meristem enlargement, the production of extra flowers and floral organs, and a decrease in floral meristem determinacy. To investigate whether ULT1 functions in known meristem regulatory pathways, we generated double mutants between ult1 alleles and null alleles of the meristem-promoting genes SHOOTMERISTEMLESS (STM) and WUSCHEL (WUS). We found that, although the ult1 alleles have no detectable embryonic or vegetative phenotypes, ult1 mutations restored extensive organ-forming capability to stm null mutants after germination and increased leaf and floral organ production in stm partial loss-of-function mutants. Mutations in ULT1 also partially suppressed the wus shoot and floral meristem phenotypes. However, wus was epistatic to ult1 in the center of the flower, and WUS transcriptional repression was delayed in ult1 floral meristems. Our results show that during the majority of the Arabidopsis life cycle, ULT1 acts oppositely to STM and WUS in maintaining meristem activity and functions in a separate genetic pathway. However, ULT1 negatively regulates WUS to establish floral meristem determinacy, acting through the WUS-AG temporal feedback loop.

Arabidopsis↗