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At least 181 records · Page 10Linked to original sources
PubMed2003

Regulatory gene mutations affecting apolipoprotein gene expression: functions and regulatory behavior of known genes may guide future pharmacogenomic approaches to therapy.

A pharmacogenomic approach to therapy requires systematic knowledge of the regulatory regions of the genes, as well as basic understanding of transcriptional regulatory mechanisms of genes. Using the apolipoprotein (apo) A-I/CIII gene cluster as a model system, we have identified by in vitro and in vivo studies the regulatory elements and the factors which control its transcription. Studies in transgenic mice established that the hepatocyte nuclear factor (HNF-4) binding site of the apoCIII enhancer, which controls transcription of both genes, is required for the intestinal expression of apoA-I and apoCIII genes, and enhances synergistically their hepatic transcription in vivo. The three Sp1 sites of the enhancer are also required for the intestinal expression of apoA-land apoCIII genes in vivo, and for the enhancement of the hepatic transcription. The regulation of the apoE/apoCI/apoCIV/apoCII cluster is also cited. It is expected that identification of the regulatory regions of genes will be soon accelerated by the sequencing of several mammalian genomes. The functional analyses of the regulatory domains of genes involved in lipid homeostasis, combined with cross-species sequence comparisons in the near future, may identify natural regulatory gene polymorphisms in the general population that will permit rational pharmacogenomic approaches for treatment of dyslipidemias.

Animals↗
PubMed1992

The IR3 gene of equine herpesvirus type 1: a unique gene regulated by sequences within the intron of the immediate-early gene.

The complete nucleotide sequence of the inverted repeat component (IR; 12,776 bp each) of the genome of equine herpesvirus type 1 (EHV-1) has been determined. Transcription analyses have revealed that the EHV-1 IR sequence encodes at least 6 genes. In this report, we present the DNA sequence and transcriptional characterization of a gene (IR3) that maps entirely within the IR sequences. The IR3 open reading frame (ORF) is located between nucleotides (nt) 6123-6411 of the IR sequence and possesses an ORF of 95 amino acids. Interestingly, this ORF does not show homology to any known herpesvirus gene, suggesting that the IR3 gene is unique to EHV-1. Moreover, the location of the IR3 gene between the immediate-early (IR1) gene and the origin of replication is unique in comparison to the IR gene arrangement of other alphaherpesviruses such as herpes simplex virus type 1 and varicella zoster virus. Putative cis-acting elements flanking the IR3 ORF include a TATA box (nt 5648-5652), a GC box (nt 5600-5605), and three polyadenylation signals (nt 6533-6538, 6648-6653, and 6663-6668). Northern blot analyses identified a 1.0 kb mRNA that exhibits characteristics of a late gene of the gamma-1 class. Northern blot, S1 nuclease, and primer extension analyses revealed that transcription of IR3 initiates within the intron of the immediate-early gene (IR1) on the opposite stand of the genome. Thus, the 5' end of IR3 transcript is antisense to the 5' end of the IR1 mRNA and promoter, and IR3 transcription may regulate the expression of IR1 during late times of infection.

Animals↗
PubMed2005

The genes and gene organization of the Ly49 region of the rat natural killer cell gene complex.

We here report the cDNA sequences of 11 new rat Ly49 genes with full and three with incomplete open reading frames. Although obtained from different inbred rat strains, these as well as six previously published cDNA represent non-allelic genes matching different loci in the Brown Norway (BN) rat genome, which is predicted to contain 34 Ly49 loci distributed over the distal part of the NK cell gene complex. Some of the cloned genes appear to be mutated to non-function in the BN genome, which harbors additional genes with full open reading frames, suggesting at least 26 non-allelic functional Ly49 genes in the rat. Of the encoded receptors, 13 are predicted to be inhibitory, eight to be activating, whereas five may be both ('bifunctional'). Phylogenetic analysis bears evidence of a highly dynamic genetic region, in which only the most distally localized Ly49 gene has a clear-cut mouse ortholog. In phylograms, the majority of the genes cluster into three subgroups with the genes mapping together, defining three chromosomal regions that seem to have undergone recent expansions. When comparing the lectin-like domains, the receptors form smaller subgroups, most containing at least one inhibitory and one activating or 'bifunctional' receptor, where close sequence similarities suggest recent homogenization events.

Alleles↗
PubMed2003

TGFbeta directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes.

In experimental autoimmune encephalomyelitis, the acute phase of the disease is produced by T-helper lymphocyte type 1 (TH1), which produces mainly TNFalpha and IFNgamma. Recovery from the disease is mediated by T-helper lymphocyte types 2 and 3 (TH2/TH3), which, among other cytokines, produce transforming growth factor beta (TGFbeta). To address the influence of TGFbeta on TH1-induced gene expression, microarray technology was used on murine primary microglial cells stimulated with IFNgamma and TNFalpha in the absence or presence of TGFbeta. The resulting data from an investigation of up to 5,500 genes provided the notion that TGFbeta prevents the induction of a proinflammatory gene program within microglia exposed to a TH1 milieu. TH1 cytokines upregulated 175 genes comprising cytokine, chemokine, and genes involved in host response to infection and the TNFalpha/IFNgamma intracellular signaling pathway. It is observed that TGFbeta inhibits expression of 25% of the TNFalpha/IFNgamma-induced genes and a further 66 TNFalpha/IFNgamma-independent genes. The focus of TGFbeta inhibition is observed to be directed in genes involved in chemotaxis (IL-15, CXCL1, CXCL2, CCL3, CCL4, CCL5, CCL9), chemokine receptors (CCR5, CCR9), LIF receptor, and FPR2, and on genes mediating cell migration (MMP9, MMP13, MacMARCKS, endothelin receptor B, Ena/VASP, Gas7), apoptosis (FAS, TNF, TNF receptor, caspase-1 and -11), and host response to infection (toll-like receptor 6, Mx-1, and MARCO). Taken collectively, the data strongly suggest that one of the main effects of TGFbeta is to impair cell entry into the CNS and to hinder migration of microglia in the CNS parenchyma.

Animals↗
PubMed1996

cDNA cloning and chromosomal localization of the genes encoding the alpha- and beta-subunits of human Rab geranylgeranyl transferase: the 3' end of the alpha-subunit gene overlaps with the transglutaminase 1 gene promoter.

We have isolated and sequenced the complete coding sequences of the human genes for the alpha- and beta-subunits of Rab geranylgeranyl transferase (Rab GGTase). The alpha- and beta-subunit genes code for proteins of 567 and 331 amino acids, respectively, showing 91 and 95% amino acid identity to their rat counterparts. We employed fluorescence in situ hybridization to map the beta-subunit gene to human chromosome 1p31. The alpha-subunit gene could be assigned to 14q11.2, less than 2 kb upstream of the transcription initiation site of the gene for transglutaminase 1 (TGM1). The two genes are arranged in tandem in a head-to-tail orientation. The short intergenic sequence between the two loci contains several promoter elements that are involved in the induction of TGM1 gene expression in squamous cells. These results suggest that cis-acting factors for cell-type-specific transcription of one gene are located within the transcribed region of a functionally unrelated gene.

Alkyl and Aryl Transferases↗
PubMed2000

Characterization of the human TBX20 gene, a new member of the T-Box gene family closely related to the Drosophila H15 gene.

T-box transcription factors contain a novel type of DNA-binding domain, the T-box domain, and are encoded by an ancient gene family. Four T-box genes, omb, Trg, org-1, and H15, have been identified in Drosophila, whereas in mammals the T-box gene family has expanded, and 12 human T-box genes have been isolated. We have identified a new human T-box gene, TBX20, and its mouse homologue Tbx20, which are more closely related to the Drosophila H15 gene than to any known vertebrate gene. H15 expression in leg imaginal discs correlates with commitment to a ventral fate, implicating this gene in early patterning events. We find that TBX20 is expressed in the fetal heart, eye, and limb, and during embryogenesis in the mouse, Tbx20 is expressed in the developing heart, eye, ventral neural tube, and limbs, indicating a possible role in regulating development of these tissues. The TBX20 gene maps to chromosome 7p14-p15. An association between TBX20 and loci for retinitis pigmentosa, RP9, and blepharophimosis syndrome, BPES, have been excluded.

Amino Acid Sequence↗
PubMed2002

Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population.

A mutation in coagulant factor V gene, a substitution in the 3' untranslated region of prothrombin gene, and a variant in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be related to venous thromboembolism in Caucasians, but this relationship remains in debate in other populations. In this case-control study, we aimed to determine the prevalence of these three mutations in the Chinese population and investigate whether they are associated with pulmonary thromboembolism. The subjects consisted of 90 patients with pulmonary thromboembolism and 143 age- and sex-matched healthy controls. Traditional risk factors for venous thrombosis and pulmonary thromboembolism were investigated as well. We found that the frequencies of varicose vein, phlebitis, trauma, and surgery were significantly higher in cases than in controls. Of all subjects, none was a carrier of coagulant factor V gene G1691A mutation or prothrombin gene G 20210A mutation, which are common point mutations in Caucasians, while the frequency of MTHFR gene 677T allele exceeded 55% in cases (56.7%), controls (55.2%), and all subjects (55.8%) studied. The homozygous mutation rate of MTHFR gene was over 30% in both cases (33.3%) and controls (32.2%), but no significant difference was found in genotype distribution (chi(2)=0.100, P=0.951). Model fitting using logistic regression did not find that MTHFR gene C677T mutation was associated with pulmonary thromboembolism, consistent with the results of stratification analysis. In conclusion, coagulant factor V gene G1691A mutation and prothrombin G20210A mutation are very rare, while MTHFR C677T mutation is very common, and all of them are not associated with pulmonary thromboembolism in the Chinese population.

Case-Control Studies↗
PubMed1996

Compartmentalization of genes coding for immunodominant antigens to fragile chromosome ends leads to dispersed subtelomeric gene families and rapid gene evolution in Plasmodium falciparum.

Recent studies on the chromosome structure of Plasmodium falciparum have led to two observations: chromosome breakage occurs frequently in subtelomeric regions and the genes coding for a number of immunodominant parasite proteins are located in these fragile chromosomal segments. Toward understanding the biological significance of these observations, we have been studying the variability of a number of these telomeric genes in parasite lines isolated in different regions of the world. In this report, we present evidence that the telomeric location of the resa and the gbp genes of P. falciparum has allowed their dispersion to other chromosomes and eventual alteration. In the first example it is shown that the resa gene has been dispersed to subtelomeric positions on chromosomes 1, 2, 11 and 14 in clinical isolates from West African patients, giving rise to new parasite genotypes and gene linkage groups. Cloning and molecular analysis of the newly detected resa-related sequences reveal that two of the members of the family have diverged from the ancestral copy on chromosome 1, while the third member on chromosome 14 is very homologous to the ancestral copy indicating that it arose from a recent translocation event. In the second example, we show that the gbp genes form a dispersed gene family that maps to at least three different chromosome extremities. The data suggest that the compartmentalization of P. falciparum antigen genes to the chromosome ends lead to gene families scattered on several chromosome extremities. We propose that the generation of segmental aneuploidy is a specific mechanism of genome adaptation of P. falciparum to its host environment. We present a model to explain the duplicative translocation of chromosome termini.

Amino Acid Sequence↗
PubMed2000

Mapping of the chicken immunoglobulin heavy-chain constant region gene locus reveals an inverted alpha gene upstream of a condensed upsilon gene.

Chicken antibodies are increasingly being used as diagnostic and therapeutic tools. As only the genomic organization of the micro encoding gene was previously known, we analysed the chicken immunoglobulin Y (IgY) and IgA (upsilon and alpha chain) immunoglobulin heavy-chain constant region (IGHC) genes and the organization of the chicken IGHC locus. The alpha gene is encoded by four separate exons, whereas, surprisingly, there is no intervening DNA sequence between the CH1 and CH2 domains of the IgY heavy chain, which is thus encoded by three exons separated by two introns. DNA sequence analysis shows that the exon boundaries of the chicken IGHC genes are not consistent with published domain borders. Furthermore, differences in DNA sequence confirm the existence of IgY, IgA and IgM allotypes in chickens. Finally, our results show that the IGHC genes of chicken (IgY, IgA and IgM) are all colocated on chromosome E18C15W15, where the alpha gene is located upstream of the upsilon gene in an inverted transcriptional orientation. The distances between the mu and alpha genes and the alpha and upsilon genes are about 18 and 15 kilobases, respectively, and thus, the size of the whole chicken IGHC locus is approximately 67 kilobases.

Animals↗
PubMed1998

Evolution, organization, and expression of alpha-tubulin genes in the antarctic fish Notothenia coriiceps. Adaptive expansion of a gene family by recent gene duplication, inversion, and divergence.

To assess the organization and expression of tubulin genes in ectothermic vertebrates, we have chosen the Antarctic yellowbelly rockcod, Notothenia coriiceps, as a model system. The genome of N. coriiceps contains approximately 15 distinct DNA fragments complementary to alpha-tubulin cDNA probes, which suggests that the alpha-tubulins of this cold-adapted fish are encoded by a substantial multigene family. From an N. coriiceps testicular DNA library, we isolated a 13.8-kilobase pair genomic clone that contains a tightly linked cluster of three alpha-tubulin genes, designated NcGTbalphaa, NcGTbalphab, and NcGTbalphac. Two of these genes, NcGTbalphaa and NcGTbalphab, are linked in head-to-head (5' to 5') orientation with approximately 500 bp separating their start codons, whereas NcGTbalphaa and NcGTbalphac are linked tail-to-tail (3' to 3') with approximately 2.5 kilobase pairs between their stop codons. The exons, introns, and untranslated regions of the three alpha-tubulin genes are strikingly similar in sequence, and the intergenic region between the alphaa and alphab genes is significantly palindromic. Thus, this cluster probably evolved by duplication, inversion, and divergence of a common ancestral alpha-tubulin gene. Expression of the NcGTbalphac gene is cosmopolitan, with its mRNA most abundant in hematopoietic, neural, and testicular tissues, whereas NcGTbalphaa and NcGTbalphab transcripts accumulate primarily in brain. The differential expression of the three genes is consistent with distinct suites of putative promoter and enhancer elements. We propose that cold adaptation of the microtubule system of Antarctic fishes is based in part on expansion of the alpha- and beta-tubulin gene families to ensure efficient synthesis of tubulin polypeptides.

Amino Acid Sequence↗
PubMed1985

The petunia chlorophyll a/b binding protein genes: a comparison of Cab genes from different gene families.

In Petunia (Mitchell) there are at least 16 genes which encode the chlorophyll a/b binding proteins; these genes have been classified into small multigene families based upon nucleotide sequence homology (1). A gene from each of five distinct Cab gene families is compared here. These genes have uninterrupted open reading frames of 266 or 267 amino acids corresponding to the Cab precursor proteins of sizes around 32000 daltons. A comparison of the amino acid sequences deduced here with published information from direct NH2-terminal analysis of a mature Cab protein in pea (10) suggests that a 34-36 amino acid transit peptide is cleaved from the NH2-terminal of the petunia precursor proteins. The proposed transit peptide sequences are more divergent than the mature peptide sequences between the Cab genes from different gene families. There are two regions within the mature Cab proteins which are conserved between all genes--a sequence of 28 amino acids near the NH2 terminal, and another sequence of 26 amino acids in the middle of the protein. The DNA sequences proximal to the Cab coding regions contain typical eukaryote promoter elements--TATA and CCAAT boxes, and in addition those genes which are known to be expressed in petunia leaf tissue also have an extensive region of homology (48 nucleotides) centered at approximately 130 nucleotides from the proposed transcription start sites.

Amino Acid Sequence↗
PubMed2004

Antagonistic interactions between the SA and JA signaling pathways in Arabidopsis modulate expression of defense genes and gene-for-gene resistance to cucumber mosaic virus.

Gene-for-gene resistance to a yellow strain of cucumber mosaic virus [CMV(Y)] is conferred by the dominant RESISTANCE to CMV(Y) (RCY1) allele in the Arabidopsis thaliana ecotype C24. RCY1-conferred resistance to CMV(Y) and expression of the Pathogenesis-related 1 (PR-1) and PR-5 genes are partially compromised by the eds5 mutation and the nahG transgene that block accumulation of salicylic acid (SA). In contrast, the RCY1-conferred resistance to CMV(Y) is not affected by the jasmonic acid (JA)-insensitive coi1 and jar1 mutations. Interestingly, we report here that in contrast to the eds5 RCY1 plant, the eds5 coi1 RCY1 double-mutant plant exhibited a higher level of resistance to CMV(Y). Presence of the coi1 mutant allele also restored the CMV(Y)-activated expression of the PR-1 and PR-5 gene in the eds5 coi1 RCY1 plant. In contrast to the PR-1 and PR-5 genes, expression of the JA-dependent PLANT DEFENSIN 1.2 (PDF1.2) and HEVEIN-LIKE PROTEIN (HEL) genes was elevated in the CMV(Y)-inoculated leaves of the eds5 RCY1 plant, but not in the virus-inoculated leaves of the wild-type RCY1 and coi1 RCY1 plants. We propose that antagonistic interactions between the SA and JA signaling mechanisms modulate defense gene expression and the activation of RCY1-conferred gene-for-gene resistance to CMV(Y).

Arabidopsis↗
PubMed1995

The L6 gene for flax rust resistance is related to the Arabidopsis bacterial resistance gene RPS2 and the tobacco viral resistance gene N.

The L6 rust resistance gene from flax was cloned after tagging with the maize transposable element Activator. The gene is predicted to encode two products of 1294 and 705 amino acids that result from alternatively spliced transcripts. The longer product is similar to the products of two other plant disease resistance genes, the tobacco mosaic virus resistance gene N of tobacco and the bacterial resistance gene RPS2 of Arabidopsis. The similarity involves the presence of a nucleotide (ATP/GTP) binding site and several other amino acid motifs of unknown function in the N-terminal half of the polypeptides and a leucine-rich region in the C-terminal half. The truncated product of L6, which lacks most of the leucine-rich C-terminal region, is similar to the truncated product that is predicted from an alternative transcript of the N gene. The L6, N, and RPS2 genes, which control resistance to three widely different pathogen types, are the foundation of a class of plant disease resistance genes that can be referred to as nucleotide binding site/leucine-rich repeat resistance genes.

Alternative Splicing↗
PubMedDate not supplied

Gene-gene and gene-environmental interactions of p53, p21, and IRF-1 polymorphisms in Korean women with cervix cancer.

BACKGROUND: The aim of this study was to identify gene-gene and gene-environmental factors affecting cervix carcinogenesis in Korean women. METHODS: We evaluated 530 subjects composed of 185 female cervix cancer patients and 345 normal healthy women. The single nucleotide polymorphisms (SNPs) of p53 codon 72, p21 codon 31, and interferon regulatory factor-1 (IRF-1) intron 6 were evaluated from extracted DNA of peripheral blood with an automatic DNA sequencer. The differences of each SNP, gene-gene and gene-environmental interactions between normal controls and patients were evaluated in the adjusted environmental background. RESULTS: In the environmental aspect, the rate of cervix cancer increased in the women with a lower level of education, a younger age at first sexual intercourse and more childbearing. The women who had p53 (Arg/Arg), IRF-1 (T/T), and <6 years of education showed a 14.7-fold increased risk of cervix cancer compared to the women who had p53 ( approximately Pro), IRF-1 ( approximately C), and >15 years of education. The women who had p53 (Arg/Arg), p21 (Ser/Ser), and >3 children showed a 6.4-fold increased risk of cervix cancer compared to the women who had p53 ( approximately Pro), p21 ( approximately Arg), and no children. The women who had p53 (Arg/Arg), IRF-1 (T/T), and first sexual intercourse before 22 years old showed a 5.5-fold increased risk of cervix cancer compared to the women who had p53 ( approximately Pro), IRF-1 ( approximately C), and first sexual intercourse after 26 years old. CONCLUSIONS: We found that the level of education, the age at first intercourse, and the number of children were independent risk factors in cervix carcinogenesis. The specific combinations of p53, p21, and IRF-1 gene-gene and gene-environmental interactions were significantly noted in the cervix carcinogenesis of Korean women.

Adult↗
PubMed1991

Characterization of the Cephalosporium acremonium pcbAB gene encoding alpha-aminoadipyl-cysteinyl-valine synthetase, a large multidomain peptide synthetase: linkage to the pcbC gene as a cluster of early cephalosporin biosynthetic genes and evidence of multiple functional domains.

A 24-kb region of Cephalosporium acremonium C10 DNA was cloned by hybridization with the pcbAB and pcbC genes of Penicillium chrysogenum. A 3.2-kb BamHI fragment of this region complemented the mutation in the structural pcbC gene of the C. acremonium N2 mutant, resulting in cephalosporin production. A functional alpha-aminoadipyl-cysteinyl-valine (ACV) synthetase was encoded by a 15.6-kb EcoRI-BamHI DNA fragment, as shown by complementation of an ACV synthetase-deficient mutant of P. chrysogenum. Two transcripts of 1.15 and 11.4 kb were found by Northern (RNA blot) hybridization with probes internal to the pcbC and pcbAB genes, respectively. An open reading frame of 11,136 bp was located upstream of the pcbC gene that matched the 11.4-kb transcript initiation and termination regions. It encoded a protein of 3,712 amino acids with a deduced Mr of 414,791. The nucleotide sequence of the gene showed 62.9% similarity to the pcbAB gene encoding the ACV synthetase of P. chrysogenum; 54.9% of the amino acids were identical in both ACV synthetases. Three highly repetitive regions occur in the deduced amino acid sequence of C. acremonium ACV synthetase. Each is similar to the three repetitive domains in the deduced sequence of P. chrysogenum ACV synthetase and also to the amino acid sequence of gramicidin synthetase I and tyrocidine synthetase I of Bacillus brevis. These regions probably correspond to amino acid activating domains in the ACV synthetase protein. In addition, a thioesterase domain was present in the ACV synthetases of both fungi. A similarity has been found between the domains existing in multienzyme nonribosomal peptide synthetases and polyketide and fatty acid synthetases. The pcbAB gene is linked to the pcbC gene, forming a cluster of early cephalosporin-biosynthetic genes.

Acremonium↗
PubMed2000

Genes and hypertension: from gene mapping in experimental models to vascular gene transfer strategies.

Human essential hypertension is a complex, multifactorial, quantitative trait under a polygenic control. Several strategies have been developed over the last decade to dissect genetic determinants of hypertension. Of these, the most successful have been studies that identified rare mendelian syndromes in which a single gene mutation causes high blood pressure. The attempts to identify multiple genes, each with a small contribution to the common polygenic form of hypertension, have been less successful. Several laboratories focused their attention on rat models of genetic hypertension, which can be considered as a reductionist paradigm for human disease. Using numerous crosses between hypertensive and normotensive strains, investigators identified several quantitative trait loci (QTL) for blood pressure subphenotypes and for cardiovascular complications such as left ventricular hypertrophy, kidney failure, stroke, and insulin resistance. Furthermore, congenic strains have been produced to confirm the existence of some of these QTL and to narrow down the chromosomal regions of interest. A number of interesting strategies have been developed, including a "speed" congenic strategy perfected by our group in Glasgow. However, the limit of congenic strategy is estimated at 1 cM, which corresponds to 2x10(6) base pairs of DNA and approximately 50 candidate genes. It is envisaged that gene expression profiling with cDNA microarrays might allow a quick progression toward the gene identification within cardiovascular QTL. In parallel experimental effort, several laboratories have been developing gene transfer/therapy strategies with adenoviral or adeno-associated viral vectors used, for example, to overexpress protective vascular genes such as vascular endothelial growth factor or endothelial nitric oxide synthase. It is anticipated that further developments in positional cloning of susceptibility and severity genes in hypertension and its complications will lead to a direct transfer of these discoveries to essential hypertension in humans and will ultimately produce novel targets for local and systemic gene therapy in cardiovascular disease.

Animals↗
PubMed2005

Genome-wide structural and evolutionary analysis of the P450 monooxygenase genes (P450ome) in the white rot fungus Phanerochaete chrysosporium: evidence for gene duplications and extensive gene clustering.

BACKGROUND: Phanerochaete chrysosporium, the model white rot basidiomycetous fungus, has the extraordinary ability to mineralize (to CO2) lignin and detoxify a variety of chemical pollutants. Its cytochrome P450 monooxygenases have recently been implied in several of these biotransformations. Our initial P450 cloning efforts in P. chrysosporium and its subsequent whole genome sequencing have revealed an extraordinary P450 repertoire ("P450ome") containing at least 150 P450 genes with yet unknown function. In order to understand the functional diversity and the evolutionary mechanisms and significance of these hemeproteins, here we report a genome-wide structural and evolutionary analysis of the P450ome of this fungus. RESULTS: Our analysis showed that P. chrysosporium P450ome could be classified into 12 families and 23 sub-families and is characterized by the presence of multigene families. A genome-level structural analysis revealed 16 organizationally homogeneous and heterogeneous clusters of tandem P450 genes. Analysis of our cloned cDNAs revealed structurally conserved characteristics (intron numbers and locations, and functional domains) among members of the two representative multigene P450 families CYP63 and CYP505 (P450foxy). Considering the unusually complex structural features of the P450 genes in this genome, including microexons (2-10 aa) and frequent small introns (45-55 bp), alternative splicing, as experimentally observed for CYP63, may be a more widespread event in the P450ome of this fungus. Clan-level phylogenetic comparison revealed that P. chrysosporium P450 families fall under 11 fungal clans and the majority of these multigene families appear to have evolved locally in this genome from their respective progenitor genes, as a result of extensive gene duplications and rearrangements. CONCLUSION: P. chrysosporium P450ome, the largest known to date among fungi, is characterized by tandem gene clusters and multigene families. This enormous P450 gene diversity has evolved by extensive gene duplications and intragenomic recombinations of the progenitor genes presumably to meet the exceptionally high metabolic demand of this biodegradative group of basidiomycetous fungi in ecological niches. In this context, alternative splicing appears to further contribute to the evolution of functional diversity of the P450ome in this fungus. The evolved P450 diversity is consistent with the known vast biotransformation potential of P. chrysosporium. The presented analysis will help design future P450 functional studies to understand the underlying mechanisms of secondary metabolism and oxidative biotransformation pathways in this model white rot fungus.

Alternative Splicing↗
PubMedDate not supplied

Mutations of the cell cycle regulatory genes p16INK4A and p21WAF1 and the metastasis-inducing gene S100A4 are infrequent and unrelated to p53 tumour suppressor gene status and data on survival in oropharyngeal squamous cell carcinomas.

BACKGROUND: Oropharyngeal squamous cell carcinoma (SCC) is probably the most serious cancer to be encountered in the clinic. MATERIALS AND METHODS: Exons 1-3 of the p16 and exon 2 of the p21 genes were examined for mutations by polymerase chain reaction (PCR)/direct DNA sequencing methods in 21 fresh-frozen tissue specimens of oropharyngeal SCCs previously studied for expression and mutation (exons 5-9) of the p53 gene. Mutations in exons 2 and 3 of the S100A4 gene were studied in 10 cases. Findings were examined for correlations with patients' clinicopathological parameters and data on survival. RESULTS: No p16 gene mutations were found in any of the cases examined. Only one tumour, which previously had shown expression and mutation in the p53, had a point mutation at codon 117 of exon 2 of the p21 gene with a resulting Cys-->Tyr amino acid substitution. Exons 2 and 3 of the S100A4 gene were not found mutated in the cases studied. Analysis of survival data showed that, among the 60% (12 out of 20) of patients who died, 50% (6 out of 12) had mutations in p53 while the remaining 50% had no mutations. Of the 50% with mutated p53, 17% (1 out of 6) also had mutation in p21. For the 40% (8 out of 20) who are alive, 63% (5 out of 8) had mutations in p53 and 37% (3 out of 8) had no mutations. CONCLUSION: These findings demonstrate that: (i) mutations of the cell cycle regulatory genes p16 and p21 and the S100A4 gene are infrequent and might be unnecessary in development and/or progression of oropharyngeal SCCs, (ii) the results were not found to relate to previous results of p53, (iii) loss of p21 and/or p53 might not predict for prognosis in these cancers, (iv) the absence of mutations of the three genes examined in the cases previously found mutated for p53 might suggest that these mutations are complementary to p53 mutations in the development of these cancers, but the lack of these mutations in the cases with no mutations in p53 might suggest that the pathogenesis of these cancers may follow other independent pathways. Since p53 and pRb (p16/pRb/cyclin-D1) pathways represent the two main mechanisms for cell cycle control at the G1-S checkpoint, further studies are necessary to examine the possible alterations in the pRb (p16/pRb/cyclin-D1) and the p53 pathways in oropharyngeal SCCs.

Alcohol Drinking↗