A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer.

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
Nature Genetics (Impact Factor: 29.65). 07/2005; 37(6):590-2. DOI: 10.1038/ng1571
Source: PubMed

ABSTRACT We examined the coding sequence of 518 protein kinases, approximately 1.3 Mb of DNA per sample, in 25 breast cancers. In many tumors, we detected no somatic mutations. But a few had numerous somatic mutations with distinctive patterns indicative of either a mutator phenotype or a past exposure.

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    ABSTRACT: BACKGROUND: Colorectal cancer (CRC) is the most common cancer worldwide. Both genetic and environmental factors play an important role in pathogenesis of CRC, susceptibility may be modified by functional polymorphisms in receptor tyrosine kinase genes, such as ErbB4. We here evaluated whether a 12-bp insertion/deletion (indel) polymorphism (rs6147150) in the 3'UTR of ErbB4 could potentially affect the occurrence of CRC in Chinese population. METHODS: We studied the genotypic and allelic frequencies of ErbB4 polymorphism in 399 patients with CRC and 419 control participants using polymerase chain reaction and polyacrylamide gel electrophoresis method. RESULTS: Under co-dominant model, we found that the del/del genotype of indel was associated with a significantly increased risk of CRC compared with its homozygote ins/ins (adjusted OR = 1.70, 95%CI = 1.06-2.71). Under recessive model, carrying of del/del genotype conferred a significantly increased risk for CRC compared with ins/ins and ins/del genotype (adjusted OR = 1.60, 95%CI = 1.03-2.50). Presence of 12-bp deletion allele of ErbB4 seemed to confer higher risk for CRC when compared with non-carriers (adjusted OR = 1.27, 95%CI = 1.02-1.57). Further stratification analysis showed that this association was more pronounced in patients with drinking. CONCLUSION: Our data suggested that individuals in Chinese population with the ErbB4 12-bp deletion allele may be at higher risk for CRC, rs6147150 would potentially be a promising novel biomarker for CRC susceptibility. Further validation of our results in larger populations and studies with functional assays are required.
    Cancer biomarkers: section A of Disease markers 01/2014; 14(6):435-9. DOI:10.3233/CBM-140420 · 1.19 Impact Factor
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    ABSTRACT: ABSTRACT NFκB signaling plays a significant role in human disease, including breast and ovarian carcinoma, insulin resistance, embryonic lethality and liver degeneration, rheumatoid arthritis, ageing and Multiple Myeloma (MM). Inhibitor of κB (IκB) kinase β (IKKβ) regulates canonical Nuclear Factor κB (NFκB) signaling in response to inflammation and cellular stresses. NFκB activation requires Lys63-linked (K63-linked) ubiquitination of upstream proteins such as NEMO or TAK1, forming molecular complexes with membrane-bound receptors. We demonstrate that IKKβ itself undergoes K63-linked ubiquitination. Mutations in IKKβ at Lys171, identified in Multiple Myeloma and other cancers, lead to a dramatic increase in kinase activation and K63-linked ubiquitination. These mutations also result in persistent activation of STAT3 signaling. Liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS) analysis identified Lys147, Lys418, Lys555 and Lys703 as predominant ubiquitination sites in IKKβ. Specific inhibition of the UBC13-UEV1A complex responsible for K63-linked ubiquitination establishes Lys147 as the predominant site of K63-ubiquitin conjugation and responsible for STAT3 activation. Thus, IKKβ activation leads to ubiquitination within the kinase domain and assemblage of a K63-ubiquitin conjugated signaling platform. These results are discussed with respect to the importance of upregulated NFκB signaling known to occur frequently in MM and other cancers.
    Cell cycle (Georgetown, Tex.) 12/2014; DOI:10.4161/15384101.2014.988026 · 5.01 Impact Factor
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    ABSTRACT: Background Right open reading frame protein kinase 3 (RIOK-3) belongs to the atypical kinase family. Unlike the other two members, RIOK-1 and RIOK-2, which are conserved from Archaea to humans, RIOK-3 occurs only in multicellular organisms. Studies on HeLa cells indicate that human RIOK-3 is a component of the 40S small ribosome subunit and supports cancer cell growth and survival. However, almost nothing is known about the function of RIOK-3. We explored the functional role of RIOK-3 encoding gene from Strongyloides stercoralis, a parasitic nematode of humans and dogs.Methods To analyze the gene and promoter structure of Ss-riok-3, RACE-PCR and Genome-walker PCR were performed to isolate the full length cDNA, gDNA and promoter region of Ss-riok-3. RNA-seq was conducted to assess the transcript abundance of Ss-riok-3 in different stages of S. stercoralis. Transgenesis was employed to determine the anatomic expression patterns of Ss-riok-3.ResultsThe RIOK-3 protein-encoding gene (designated Ss-riok-3) of S. stercoralis was characterized. The full-length complementary and genomic DNAs of the RIOK-3 encoding gene (riok-3) were isolated from this nematode. The cDNA of Ss-riok-3 is 1,757 bp in length, including a 23 bp 5¿-UTR, a 36 bp 3¿-UTR and a 1,698 bp coding region encoding a protein of 565 amino acids (aa) containing a RIO kinase domain. RNA sequencing (RNA-seq) analysis revealed that Ss-riok-3 is transcribed in all developmental stages of S. stercoralis assessed, with transcripts being particularly abundant in parasitic females. Gene structure analysis revealed that Ss-riok-3 contains no intron. The putative promoter contains conserved promoter elements, including four TATA, two GATA, one inverse GATA and one inverse CAAT boxes. The promoter of Ss-riok-3 drives GFP expression in the head neuron, intestine and body wall muscle of transgenic S. stercoralis larvae, and the TATA boxes present in the 3¿-UTR of the gene immediately upstream of Ss-riok-3 initiate transcription.Conclusions The characterization of the RIOK-3 encoding gene from S. stercoralis provides a sound foundation for investigating in detail its function in the development and reproduction of this important pathogen.
    Parasites & Vectors 12/2014; 7(1):561. DOI:10.1186/PREACCEPT-1041797881140939 · 3.25 Impact Factor

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