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1.
New Phytol ; 231(5): 1720-1733, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34086997

RESUMO

Wood of coniferous trees (softwood), is a globally significant carbon sink and an important source of biomass. Despite that, little is known about the genetic basis of softwood cell wall biosynthesis. Branching of xylan, one of the main hemicelluloses in softwood secondary cell walls, with glucuronic acid (GlcA) is critical for biomass recalcitrance. Here, we investigate the decoration patterns of xylan by conifer GlucUronic acid substitution of Xylan (GUX) enzymes. Through molecular phylogenetics we identify two distinct conifer GUX clades. Using transcriptional profiling we show that the genes are preferentially expressed in secondary cell wall forming tissues. With in vitro and in planta assays we demonstrate that conifer GUX enzymes from both clades are active glucuronyltransferases. Conifer GUX enzymes from each clade have different specific activities. While members of clade one add evenly spaced GlcA branches, the members of clade two are also capable of glucuronidating two consecutive xyloses. Importantly, these types of xylan patterning are present in softwood. As xylan patterning might modulate xylan-cellulose and xylan-lignin interactions, our results further the understanding of softwood cell wall biosynthesis and provide breeding or genetic engineering targets that can be used to modify softwood properties.


Assuntos
Arabidopsis , Traqueófitas , Parede Celular , Ácido Glucurônico , Melhoramento Vegetal , Traqueófitas/genética , Xilanos
2.
Nat Genet ; 36(12): 1301-5, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15543146

RESUMO

Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment. We recently identified a locus on chromosome 10p13-p12.1 involved in permanent neonatal diabetes mellitus associated with pancreatic and cerebellar agenesis in a genome-wide linkage search of a consanguineous Pakistani family. Here we report the further linkage analysis of this family and a second family of Northern European descent segregating an identical phenotype. Positional cloning identified the mutations 705insG and C886T in the gene PTF1A, encoding pancreas transcription factor 1alpha, as disease-causing sequence changes. Both mutations cause truncation of the expressed PTF1A protein C-terminal to the basic-helix-loop-helix domain. Reporter-gene studies using a minimal PTF1A deletion mutant indicate that the deleted region defines a new domain that is crucial for the function of this protein. PTF1A is known to have a role in mammalian pancreatic development, and the clinical phenotype of the affected individuals implicated the protein as a key regulator of cerebellar neurogenesis. The essential role of PTF1A in normal cerebellar development was confirmed by detailed neuropathological analysis of Ptf1a(-/-) mice.


Assuntos
Cromossomos Humanos Par 10/genética , Diabetes Mellitus/genética , Mutação/genética , Fenótipo , Fatores de Transcrição/genética , Animais , Sequência de Bases , Western Blotting , Cerebelo/patologia , Biologia Computacional , Consanguinidade , Ligação Genética , Técnicas Histológicas , Humanos , Lactente , Escore Lod , Camundongos , Camundongos Mutantes , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Pâncreas/patologia , Linhagem , Análise de Sequência de DNA
3.
Connect Tissue Res ; 51(6): 434-44, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20497018

RESUMO

Tenocytes are known to be mechanoresponsive and the present study tests the hypothesis that distinct mechanical stimulation regimes, associated with the short-term and extended application of cyclic tensile strain, alters the balance between anabolic and catabolic processes. Microarray technology has been used to provide a comprehensive analysis of alterations in gene expression within isolated tendon fascicles in response to cyclic tensile strain using a well-established model system. Isolated rat tail tendon fascicles were subjected to cyclic tensile strain (3% amplitude superimposed on a 2% static strain) for 1 or 24 hr. Messenger RNA expression level was assessed using Illumina microarray. The number of genes significantly altered in strained fascicles from the level of unstrained control fascicles was greater at 24 hr than 1 hr. The expression levels of many extracellular matrix components remained unchanged at both time points; however, a number of members of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with a thrombospondin (ADAMTS) families were significantly downregulated at 24 hr. Functional annotation revealed that upregulated genes were significantly associated with the regulation of transcription at 1 hr and translation at 24 hr. Downregulated genes were associated with inflammatory responses at 1 hr, and genes inhibited at 24 hr were significantly associated with cell apoptosis and a variety of metabolic functions. The present results suggest that the metabolic balance was shifted in favor of catabolism by the application of a small number of tensile strain cycles, whereas an extended number stimulates strong anti-catabolic effects.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Tendões/citologia , Tendões/metabolismo , Resistência à Tração/fisiologia , Animais , Colágeno/biossíntese , Colágeno/genética , Colágeno/fisiologia , Força Compressiva/fisiologia , Regulação para Baixo/genética , Regulação para Baixo/fisiologia , Proteínas da Matriz Extracelular/biossíntese , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/fisiologia , Masculino , Ratos , Ratos Wistar , Regulação para Cima/genética , Regulação para Cima/fisiologia
4.
Cancer Lett ; 196(1): 65-7, 2003 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-12860291

RESUMO

Allele imbalance at chromosome 15q14-q22 is seen in a high proportion of sporadic colorectal cancers encompassing the colorectal adenoma and carcinoma susceptibility locus. The FLJ12973 gene, which has recently been identified as a candidate tumour suppressor, maps to 15q15 and encodes a WD-repeat protein with structural similarity to the small subunit of the xeroderma pigmentosum E (XP-E) complex. To examine the proposition that FLJ12973 is involved in colorectal cancer we analysed 31 tumours for sequence variation. No missense changes or pathogenic mutations--truncating or splice site--were detected in any of the tumours. While epigenetic effects on FLJ12973 cannot be excluded, these results show that it is not a common target for mutations in colorectal cancers.


Assuntos
Cromossomos Humanos Par 15 , Neoplasias Colorretais/genética , Genes Supressores de Tumor , Humanos , Mutação
5.
Cancer Lett ; 200(2): 149-52, 2003 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-14568168

RESUMO

Aneuploidy is a characteristic of a subset of colorectal tumours. CHEK2 (also known as CHK2) is one of the cell cycle checkpoint genes coding for a family of proteins that sense damage in eukaryotic cells. Germline variation in CHEK2 has recently been shown to confer cancer susceptibility. Heterozygous mutations have been identified in patients with TP53-negative Li-Fraumeni syndrome. Furthermore, the CHEK2 1100delC variant carried by 1% of the population has been shown to act as a low penetrance allele for both breast and prostate cancers. To further our knowledge about the contribution of CHEK2 1100delC to cancer incidence we have analysed a series of 149 patients with multiple colorectal adenomas some of whom developed colorectal cancer. The CHEK2 1100delC allele was not over-represented in cases suggesting that this variant is not associated with an increased risk of colorectal disease.


Assuntos
Adenoma/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Neoplasias Primárias Múltiplas/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases , Idoso , Quinase do Ponto de Checagem 2 , Feminino , Genes Supressores de Tumor , Genes cdc , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
6.
Int J Cancer ; 119(4): 964-7, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16550608

RESUMO

Epidemiological data has implicated heterozygosity for xeroderma pigmentosum (XP) as a risk factor for lung cancer. XP has 8 known complementation groups, 7 of which are caused by mutations in genes encoding components of the nucleotide excision repair (NER) pathway. To formally investigate the role of XP-related NER genes in lung cancer susceptibility, we screened germline DNA from 92 familial early-onset lung cancer patients for mutations in all coding regions and intron-exon boundaries of XPA, XPC, XPD, XPF, XPB, XPG and DDB2. Forty-one exonic variants were identified. Twenty-four were nonsynonymous, of which 14 were previously documented polymorphisms. Ten missense variants had not been previously described; none of which were detected in germline DNA from 278 cancer-free controls. Two of the novel missense changes are predicted to be functionally deleterious. Our findings are compatible with XP heterozygosity being a risk factor for lung cancer susceptibility.


Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Xeroderma Pigmentoso/genética , Adulto , Idade de Início , Proteínas de Ligação a DNA/classificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fatores de Tempo
7.
Int J Cancer ; 109(4): 554-8, 2004 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-14991577

RESUMO

Mutations in the base excision repair gene MYH have recently been shown to confer recessive susceptibility to colorectal adenomas and carcinomas. To evaluate the contribution of germline MYH mutations to early-onset colorectal cancer, we screened a series of 358 unselected early-onset cases for germline changes in the coding sequence of the gene. Two cases harbored biallelic germline mutations (0.6%; 95% CI = 0.06-2.0) and 8 single MYH mutations (2.2%; 95% CI = 0.9-4.4). Both cases harboring biallelic MYH mutations had multiple polyps but not profuse polyposis. All cases had distally sited tumors. No biallelic mutations were detected among 354 controls. These results confirm that biallelic MYH mutations confer susceptibility to colorectal cancer but are unlikely to account for more than 3% of early-onset colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , DNA Glicosilases/genética , Variação Genética , Mutação em Linhagem Germinativa , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idade de Início , Desequilíbrio Alélico , Estudos de Casos e Controles , Colo/metabolismo , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reto/metabolismo , Reino Unido
8.
Hum Genet ; 114(2): 207-10, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14579148

RESUMO

The base excision repair gene MYH protects against damage to DNA from reactive oxygen species, which are commonly found in cigarette smoke. Inherited mutations in MYH predispose to colorectal adenomas and carcinomas that show a characteristic pattern of somatic G:C-->T:A mutations in the APC gene. A similar pattern of somatic mutations in the TP53 gene is reported in smoking-related lung cancers. We therefore tested whether germline changes in MYH may also contribute to the development of lung cancer by screening for variants in 276 patients with lung carcinoma and 106 normal controls. No patients harboured truncating mutations in MYH and only a single patient was a carrier for the G382D missense mutation. We identified three common coding region (V22M, Q324H and S501F) and intronic (157+30A>G, 462+35G>A and 1435-40G>C) variants, but none were over-represented in the patient samples, indicating that MYH variants are unlikely to predispose significantly to the risk of lung cancer.


Assuntos
DNA Glicosilases/genética , Variação Genética , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Carcinoma de Células Grandes/enzimologia , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Pequenas/enzimologia , Carcinoma de Células Pequenas/genética , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Estudos de Casos e Controles , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Éxons/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Pulmão/fisiologia , Neoplasias Pulmonares/enzimologia , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Fatores de Risco
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