Kooperativer Bibliotheksverbund

Berlin Brandenburg

and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • Mutation
Type of Medium
Language
Year
  • 1
    Language: English
    In: Nature medicine, December 2014, Vol.20(12), pp.1401-9
    Description: We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cδ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in Eμ-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.
    Keywords: Adaptor Proteins, Signal Transducing -- Genetics ; Apoptosis -- Genetics ; F-Box Proteins -- Genetics ; Lymphoma, B-Cell -- Genetics ; Lymphoma, Mantle-Cell -- Genetics ; Nerve Tissue Proteins -- Genetics ; Protein Kinase C-Delta -- Genetics ; Proto-Oncogenes -- Genetics ; Skp Cullin F-Box Protein Ligases -- Metabolism ; Ubiquitin-Protein Ligase Complexes -- Metabolism
    ISSN: 10788956
    E-ISSN: 1546-170X
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    In: Neuropsychopharmacology, 2002, Vol.26(4), p.489
    Description: Disturbances in the noradrenergic neurotransmission system have been implicated in the etiology of mood disorders. The norepinephrine transporter (NET) is a main target of antidepressant action and was shown to be dysregulated in major depression. Despite the clinical and physiological significance of NET gene regulation, little is known about the transcriptional control mechanisms governing its expression. Since it is well established that affective disorders have a genetic component with many genes of small effect contributing to the genetic susceptibility of depression, the NET gene is an interesting candidate gene for affective disorders. In a search for polymorphisms or mutations in the 5' flanging region of the NET gene we sequenced approximately 1000 bp upstream of the first codon in the NET gene promoter in 100 patients with major depression and 100 healthy controls. We identified a so far unknown T arrow right C polymorphism 182 bp upstream of the start codon in a transcriptional relevant region. In a case control association study we investigated the newly identified T-182C polymorphism and an already known G1287A polymorphism in exon 9 of the NET gene in a sample of 193 patients with major depression and 136 healthy, non-related controls. No statistical significant differences between patients and controls were found for any of the analyzed polymorphisms, either in the genotype distribution or in the allele frequencies. Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of major depression. [Neuropsychompharmacology 26:489-493, 2002]Neuropsychopharmacology (2002) 26 489-493.10.1016/S0893-133X(01)00386-4
    Keywords: Etiology ; Depression ; Exons ; Gene Polymorphism ; Affective Disorders ; Statistical Analysis ; Transcription ; Mood ; Promoters ; Antidepressants ; Neurotransmission ; Norepinephrine Transporter ; Risk Factors ; Gene Regulation ; Norepinephrine ; Codons ; Gene Frequency ; Mutation ; Behavioral and Cognitive Neuroscience;
    ISSN: 0893-133X
    E-ISSN: 1740634X
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    In: Nature Genetics, 2015, Vol.47(2), p.164
    Description: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1 p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P 〈 5 x [10.sup.-8]. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
    Keywords: Ovarian Cancer – Genetic Aspects ; Quantitative Trait Loci – Identification and Classification ; Quantitative Trait Loci – Health Aspects;
    ISSN: 1061-4036
    E-ISSN: 15461718
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    Language: English
    In: Cellular Physiology and Biochemistry, January 2006, Vol.18(1-3), pp.57-66
    Description: The KCNQ gene family comprises voltage-gated potassium channels expressed in epithelial tissues (KCNQ1, KCNQ5), inner ear structures (KCNQ1, KCNQ4) and the brain (KCNQ2-5). KCNQ4 is expressed in inner and outer hair cells of the inner ear where it influences electrical excitability and cell survival. Accordingly, loss of function mutations of the KCNQ4 gene cause hearing loss in humans and functional k.o.-mice show progressive degeneration of outer hair cells (OHCs). However, characteristic electrophysiological features of the native KCNQ4- carried current IK,n in OHCs are not recapitulated by expression of KCNQ4 channels in heterologous expression systems. This might suggest modulation of KCNQ4 by interacting KCNE ß-subunits, which are known to modify the properties of the closely related KCNQ1. The present study explored whether transcripts of the KCNE isoforms could be identified in OHC mRNA and whether the subunits modulate KCNQ4 function. RT-PCR indeed yielded transcripts of all five KCNEs in OHCs. Coexpression of the KCNE- ß-subunits with human KCNQ4 in the Xenopus laevis oocyte expression system revealed that all KCNEs modulate KCNQ4 voltage dependence, protein stability and ion selectivity of hKCNQ4 in Xenopus oocytes. The deafness-associated Jervell and Lange- Nielsen syndrome (JLNS) mutation KCNE1(D76N) impairs KCNQ4-function whereas the Romano-Ward syndrome (RWS) mutant KCNE1(S74L), which shows normal hearing in patients, does not impair KCNQ4 channel function. In conclusion, KCNEs are presumably coexpressed with KCNQ4 in hair cells from the organ of Corti and might regulate KCNQ4 functional properties, effects that could be important under physiological and pathophysiological conditions.
    Keywords: Original Paper ; Biology ; Chemistry
    ISSN: 1015-8987
    E-ISSN: 1421-9778
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Language: English
    In: Cellular Physiology and Biochemistry, November 2005, Vol.16(4-6), pp.255-262
    Description: The KCNQ gene family comprises voltage-gated potassium channels expressed in epithelial tissues (KCNQ1, KCNQ5), inner ear structures (KCNQ1, KCNQ4) and the brain (KCNQ2-5). KCNQ4 is expressed in inner and outer hair cells of the inner ear where it determines electrical excitability. Accordingly, loss of function mutations of the KCNQ4 gene cause hearing loss. Several K+ channels including the closely related KCNQ1/KCNE1 channel are regulated by the serum- and glucocorticoid-inducible kinase (SGK) family. The present study utilized the Xenopus oocyte system to explore effects of SGK isoforms on KCNQ4 mediated K+-currents: KCNQ4 channels activated in a voltage dependent manner with half maximal activation at -10 mV. The peak channel activity was significantly increased by prepulsing. Coexpression of wild type SGK1 but not coexpression of the inactive mutant K127NSGK1 significantly increased current amplitudes (by 67 %) and significantly increased the resting potential of KCNQ4 expressing oocytes. Here we describe for the first time a prepulse dependence of KCNQ4 channels with increased currents after hyperpolarizing prepulses. Coexpression of SGK1 significantly attenuated the effect of prepulsing on peak currents. Mutation of Ser to Asp or Ala in the putative phosphorylation consensus sequence in KCNQ4 significantly decreased the sensitivity to SGK1-coexpression. In conclusion, SGK1 regulates current amplitudes and kinetic properties of KCNQ4 channel activity, an effect sensitive to mutations in the SGK1 consensus sequence of the channel.
    Keywords: Original Paper ; Biology ; Chemistry
    ISSN: 1015-8987
    E-ISSN: 1421-9778
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: Cell, 18 June 2015, Vol.161(7), pp.1681-1696
    Description: We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant , mutant , mutant , and Triple-WT (wild-type). Integrative analysis reveals enrichment of mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making. An integrative analysis of cutaneous melanomas establishes a framework for genomic classification into four subtypes that can guide clinical decision-making for targeted therapies. A subset of each of the genomic classes expresses considerable immune infiltration markers that are associated with improved survival, with potential implications for immunotherapy.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    In: Nature Genetics, 2013, Vol.45(4), p.371
    Description: Journal article. TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.. European Commission Seventh Framework Programme (agreement 223175-HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10118 and C1287/A12014)
    Keywords: Genetics ; Breast Cancer Susceptibility;
    ISSN: 1061-4036
    E-ISSN: 15461718
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages