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Downstream Genes (downstream + gene)
Selected AbstractsGenes causing clefting syndromes as candidates for non-syndromic cleft lip with or without cleft palate: a family-based association studyEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 6 2008Luca Scapoli Clefts of the orofacial region are among the most common congenital defects, caused by abnormal facial development during gestation. Non-syndromic cleft lip with or without cleft palate (NSCLP) is a complex trait most probably caused by multiple interacting loci, with possible additional environmental factors. As facial clefts form part of more than 300 syndromes, one strategy for identifying the genetic causes of NSCLP could be to study candidate genes responsible for clefting syndromes. Three genes were selected for this investigation: TP63, which codes for the tumour protein p63 and causes Ectrodactyly-Ectodermal dysplasia-orofacial Cleft syndrome; JAG2, a downstream gene of TP63; and MID1, which is responsible for Opitz syndrome. A linkage disequilibrium investigation was performed with intragenic single nucleotide polymorphisms on each of these genes in a sample study of 239 patients/parents trios. Evidence which suggests that JAG2 and MID1 may play a role in NSCLP was obtained. [source] Autoregulation of the HAC1 gene is required for sustained activation of the yeast unfolded protein responseGENES TO CELLS, Issue 2 2004Naoki Ogawa Eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by activating a transcriptional induction program termed the unfolded protein response (UPR). The transcription factor Hac1p responsible for the UPR in Saccharomyces cerevisiae is tightly regulated by a post-transcriptional mechanism. HAC1 mRNA must be spliced in response to ER stress to produce Hac1p, which then activates transcription via direct binding to the cis -acting UPR element (UPRE) present in the promoter regions of its target genes. Here, we show that the HAC1 promoter itself responds to ER stress to induce transcription of its downstream gene, similarly to the KAR2 promoter; the KAR2 gene represents a major target of the UPR. Consistent with this observation, the HAC1 promoter contains an UPRE-like sequence, which is necessary and sufficient for the induction and to which Hac1p binds directly. Cells expressing the HAC1 gene from a mutant HAC1 promoter lacking the HAC1 UPRE could not maintain high levels of either unspliced or spliced HAC1 mRNA and became sensitive to ER stress when insulted for hours. Based on these results, we concluded that autoregulation of the HAC1 genes is required for sustained activation of the UPR and sustained resistance to ER stress. [source] Masters change, slaves remainBIOESSAYS, Issue 1 2003Patricia Graham Sex determination offers an opportunity to address many classic questions of developmental biology. In addition, because sex determination evolves rapidly, it offers an opportunity to investigate the evolution of genetic hierarchies. Sex determination in Drosophila melanogaster is controlled by the master regulatory gene, Sex lethal (Sxl). DmSxl controls the alternative splicing of a downstream gene, transformer (tra), which acts with tra2 to control alternative splicing of doublesex (dsx). DmSxl also controls its own splicing, creating an autoregulatory feedback loop that ensures expression of Sxl in females, but not males. A recent paper1 has shown that in the dipteran Ceratitis capitata later (downstream) steps in the regulatory hierarchy are conserved, while earlier (upstream) steps are not. Cctra is regulated by alternative splicing and apparently controls the alternative splicing of Ccdsx. However, Cctra is not regulated by CcSxl. Instead it appears to autoregulate in a manner similar to the autoregulation seen with DmSxl. BioEssays 25:1,4, 2003. © 2002 Wiley Periodicals, Inc. [source] Gene expression analyses on embryonic external genitalia: identification of regulatory genes possibly involved in masculinization processesCONGENITAL ANOMALIES, Issue 2 2008Hisayo Nishida ABSTRACT Androgen plays a crucial role in initiating and maintaining the expression of male sexual characteristics in mammals. In humans and mice, any defects along the pathway of androgen functions result in congenital urogenital abnormalities. The genital tubercle (GT), an anlage of the external genitalia, differentiates into a penis in males and a clitoris in females. Although masculinization of the external genitalia is androgen-dependent, the molecular pathway of its potential downstream genes is largely unclear. To identify the genes involved in mouse GT masculinization, we performed gene expression analyses, such as real-time quantitative polymerase chain reaction and section in situ hybridization analysis. From our studies we have identified candidate genes, Cyp1b1, Fkbp51 and MafB as potential androgen targets during mouse GT masculinization. [source] Novel genes involved in canonical Wnt/, -catenin signaling pathway in early Ciona intestinalis embryosDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 4 2008Shuichi Wada We report here characterization of five genes for novel components of the canonical Wnt/, -catenin signaling pathway. These genes were identified in the ascidian Ciona intestinalis through a loss-of-function screening for genes required for embryogenesis with morpholinos, and four of them have counterparts in vertebrates. The five genes we studied are as follows: Ci-PGAP1, a Ciona orthologue of human PGAP1, which encodes GPI (glycosylphosphatidylinositol) inositol-deacylase, Ci-ZF278, a gene encoding a C2H2 zinc-finger protein, Ci-C10orf11, a Ciona orthologue of human C10orf11 that encodes a protein with leucine-rich repeats, Ci-Spatial/C4orf17, a single counterpart for two human genes Spatial and C4orf17, and Ci-FLJ10634, a Ciona orthologue of human FLJ10634 that encodes a member of the J-protein family. Knockdown of each of the genes mimicked , -catenin knockdown and resulted in suppression of the expression of , -catenin downstream genes (Ci-FoxD, Ci-Lhx3, Ci-Otx and Ci-Fgf9/16/20) and subsequent endoderm formation. For every gene, defects in knockdown embryos were rescued by overexpression of a constitutively active form, but not wild-type, of Ci- , -catenin. Dosage-sensitive interactions were found between Ci-,-catenin and each of the genes. These results suggest that these five genes act upstream of or parallel to Ci- , -catenin in the Wnt/, -catenin signaling pathway in early Ciona embryos. [source] Human inhibitor of growth 1 inhibits hepatoma cell growth and influences p53 stability in a variant-dependent manner,HEPATOLOGY, Issue 2 2009Zhi Zhu Inhibitor of growth 1 (ING1) is a type II tumor suppressor that affects cell function by altering chromatin structure and regulating transcription. Recently, three ING1 splice variants have been cloned, but their roles in apoptosis and p53 regulation in human hepatocellular carcinoma (HCC) have not been fully elucidated. The present study found that ING1, in a variant-dependent manner, inhibited hepatoma cell proliferation and colony formation, induced apoptosis and cell cycle arrest at G0/G1 phase, and postponed tumor formation in nude mice. Expression of p33ING1b and p24ING1c variants, but not p47ING1a, was markedly reduced in HCC samples. Reverse transcription polymerase chain reaction and western blotting analysis revealed that ectopic overexpression of p33ING1b or p24ING1c variant increased the expression of p53 downstream genes such as p21waf1 and bax, and repressed bcl-2 expression (P < 0.01), whereas p47ING1a inactivated p21waf1 promoter (P < 0.01). Furthermore, we found that p33ING1b and p24ING1c repressed Mdm2 expression (P < 0.01) and competed with Mdm2 for binding to p53. Interestingly, p33ING1band p24ING1c did not directly bind to Mdm2 protein but strongly increased p14arf expression (P < 0.01) and interacted with p14arf protein to stimulate p53. Moreover, we found that ectopic overexpression of p33ING1b or p24ING1c significantly induced p53 protein acetylation at Lys-373/Lys-382 residue, but did not alter the phosphorylation status of p53. Conclusion: ING1 variants p33ING1b and p24ING1c may modulate p53 activity and subsequently inhibit hepatoma cell growth by at least two possible mechanisms: interacting with Mdm2 and p14arf to stabilize and activate p53, or increasing p53 acetylation. (HEPATOLOGY 2009.) [source] SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes,,HUMAN MUTATION, Issue 9 2008Susan M. Kiefer Abstract Mutations in SALL1 lead to the dominant multiorgan congenital anomalies that define Townes-Brocks syndrome (TBS). The majority of these mutations result in premature termination codons that would be predicted to trigger nonsense-mediated decay (NMD) of mutant mRNA and cause haploinsufficiency. Our previous studies using a gene targeted mouse model (Sall1- ,Zn) suggested that TBS phenotypes are due to expression of a truncated mutant protein, not haploinsufficiency. In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients. We prove that the same pathogenetic mechanism elucidated in mice is occurring in humans by demonstrating that truncated SALL1 protein is expressed in cells derived from a TBS patient. TBS mutant protein is capable of dominant negative activity that results in ectopic activation of two downstream genes, Nppa and Shox2, in the developing heart and limb. We propose a model for the pathogenesis of TBS in which truncated Sall1 protein causes derepression of Sall-responsive target genes. Hum Mutat 0,1,8, 2008. Published 2008 Wiley-Liss, Inc. [source] Sox9, a key transcription factor of bone morphogenetic protein-2-induced chondrogenesis, is activated through BMP pathway and a CCAAT box in the proximal promoter,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2008Qiuhui Pan Mouse embryonic fibroblasts (MEFs) can be differentiated into fully functional chondrocytes in response to bone morphogenetic protein-2 (BMP-2). The expression of Sox9, a critical transcription factor for the multiple steps of chondrogenesis, has been reported to be upregulated during this process. But the molecular mechanisms by which BMP-2 promotes chondrogenesis still remain largely unknown. The aim of the present study was therefore to investigate the underlying mechanism. In the MEFs, BMP-2 efficiently induced Sox9 expression along with chondrogenic differentiation in a time- and dose-dependent manner. SB203580, a specific inhibitor for p38 pathway, blocked BMP-2-induced chondrogenic differentiation as well as Sox9 expression and its transactivation of downstream genes. Forced expression of Smad6, a natural antagonist for BMP/Smad pathway, only inhibited Sox9 protein function without rendering any effects on its mRNA expression. A CCAAT box was identified in Sox9 promoter as the cis -elements responsible for BMP-2 stimulation. This study provides insight into the mechanisms underlying BMP-2-regulated Sox9 expression and activity in MEFs, and suggests differential roles of BMP-2/p38 and BMP-2/Smad pathways in modulating the function of Sox9 during chondrogenesis. J. Cell. Physiol. 217: 228,241, 2008. © 2008 Wiley-Liss, Inc. [source] Identification of cold-inducible downstream genes of the Arabidopsis DREB1A/CBF3 transcriptional factor using two microarray systemsTHE PLANT JOURNAL, Issue 6 2004Kyonoshin Maruyama Summary The transcriptional factor DREB/CBF (dehydration-responsive element/C-repeat-binding) specifically interacts with the dehydration-responsive element (DRE)/C-repeat (CRT) cis -acting element (A/GCCGAC) and controls the expression of many stress-inducible genes in Arabidopsis. Transgenic plants overexpressing DREB1A showed activated expression of many stress-inducible genes and improved tolerance to not only drought, salinity, and freezing but also growth retardation. We searched for downstream genes in transgenic plants overexpressing DREB1A using the full-length cDNA microarray and Affymetrix GeneChip array. We confirmed candidate genes selected by array analyses using RNA gel blot and identified 38 genes as the DREB1A downstream genes, including 20 unreported new downstream genes. Many of the products of these genes were proteins known to function against stress and were probably responsible for the stress tolerance of the transgenic plants. The downstream genes also included genes for protein factors involved in further regulation of signal transduction and gene expression in response to stress. The identified genes were classified into direct downstream genes of DREB1A and the others based on their expression patterns in response to cold stress. We also searched for conserved sequences in the promoter regions of the direct downstream genes and found A/GCCGACNT in their promoter regions from ,51 to ,450 as a consensus DRE. The recombinant DREB1A protein bound to A/GCCGACNT more efficiently than to A/GCCGACNA/G/C. [source] Mutational analysis of hypoxia-related genes HIF1, and CUL2 in common human cancersAPMIS, Issue 12 2009SANG WOOK PARK Hypoxia is a general feature of solid cancer tissues. Hypoxia upregulates hypoxia-inducible factor 1, (HIF1,) that transactivates downstream genes and contributes to cancer pathogenesis. HIF1, is upregulated not only by hypoxia but also by genetic alterations in HIF1,-related genes, including VHL. Cullin 2 (CUL2) interacts with the trimeric VHL-elongin B-elongin C complex and plays an essential role in the ubiquitinated degradation of HIF1,. The aim of this study was to explore whether HIF1, and CUL2 genes are somatically mutated, and contribute to HIF1, activation in common human cancers. For this, we have analyzed the coding region of oxygen-dependent degradation domain of HIF1, in 47 colon, 47 gastric, 47 breast, 47 lung, and 47 hepatocellular carcinomas, and 47 acute leukemias by a single-strand conformation polymorphism assay. In addition, we analyzed mononucleotide repeat sequences (A8) in CUL2 in 55 colorectal and 45 gastric carcinomas with microsatellite instability (MSI). We found one HIF1, mutation (p.Ala593Pro) in the hepatocellular carcinomas (1/47; 2.1%), but none in other cancers. We found two CUL2 frameshift mutations in colon cancers (p.Asn292MetfsX20), which were exclusively detected in high MSI cancers (4.9%; 2/41). Our data indicate that somatic mutation of HIF1, is rare in common cancers, and somatic mutation of CUL2 occurs in a fraction of colorectal cancers (colorectal cancers with high MSI). The data suggest that neither HIF1, nor CUL2 mutation may play a central role in HIF1, activation in gastric, colorectal, breast, lung and hepatocellular carcinomas, and acute leukemias. [source] Altered localization of gene expression in both ectoderm and mesoderm is associated with a murine strain difference in retinoic acid,induced forelimb ectrodactyly,BIRTH DEFECTS RESEARCH, Issue 6 2007Hirohito Shimizu Abstract BACKGROUND: Defects in digit number or fusion as a teratogenic response are well documented in humans and intensively studied in various mouse models. Maternal exposure to excess levels of all- trans -retinoic acid (RA) at gestational day 9.5 induces postaxial ectrodactyly (digit loss) in the murine C57BL/6N strain but not in the SWV/Fnn strain. METHODS: Whole-mount in situ hybridization was used to examine the differential expression of limb patterning genes at the transcriptional level between the two mouse strains following the maternal exposure to a teratogenic level of RA. The detection of a gene with altered expression was followed by either the evaluation of other genes that were synexpressed or with an assessment of downstream genes. RESULTS: In the C57BL/6N limb bud following maternal RA administration, gene-specific perturbations were observed within hours of the RA injection in the posterior pre-AER (apical ectodermal ridge) (Fgf8, Dlx3, Bmp4, Sp8, but not Dlx2 or p63), whereas these genes were normally expressed in the SWV/Fnn limb bud. Furthermore, although RA caused comparable reductions of Shh expression between the strains in the 12 h after administration, some Shh downstream genes were differentially expressed (e.g., Gli1, Ptc, and Hoxd13), whereas others were not (e.g., Fgf4, Bmp4, and Gremlin). CONCLUSIONS: It is proposed that altered gene expression in both pre-AER and mesoderm is involved in the pathogenesis of postaxial digit loss, and that because the alterations in the pre-AER occur relatively early in the temporal sequence of events, those changes are candidates for an initiating factor in the malformation. Birth Defects Research (Part A) 2007. © 2007 Wiley-Liss, Inc. [source] Isolation of p53-target genes and their functional analysisCANCER SCIENCE, Issue 1 2004Yusuke Nakamura Mutations of the p53 gene are the most common genetic alterations found in human cancers, and are known to play crucial roles in tumor development and progression. The p53 gene encodes a protein functioning as a transcription factor, and the biological functions of p53 are manifested through the activities of its downstream genes. Identification of these downstream genes involved in the p53-signaling pathway should provide more detailed insight into the molecular mechanisms that mediate tumor-suppressor activities, as well as various responses to cellular stress. We have been attempting to isolate p53-target genes by means of various approaches, including differential display, cDNA microarray analysis, and direct cloning of the p53-binding sequences from human genomic DNA. Here I review our recent work on isolation of p53-target genes and their functional analysis. The physiological functions of p53-target genes include apoptosis (GML, p53AIP1, and STAG1), DNA repair (p53R2), inhibition of angiogenesis (BAI1), re-entry into the cell cycle (p53RFP), oxidative stress (CSR), and determination of cell fate (p53RDL1). (Cancer Sci 2004; 95: 7,11) [source] | |||||||||||||||||||||||||