DDX6

Gene Summary

Gene:DDX6; DEAD (Asp-Glu-Ala-Asp) box helicase 6
Aliases: P54, RCK, HLR2
Location:11q23.3
Summary:This gene encodes a member of the DEAD box protein family. The protein is an RNA helicase found in P-bodies and stress granules, and functions in translation suppression and mRNA degradation. It is required for microRNA-induced gene silencing. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Mar 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:probable ATP-dependent RNA helicase DDX6
HPRD
Source:NCBIAccessed: 18 March, 2015

Ontology:

What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 18 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Proto-Oncogene Proteins c-myc
  • Principal Component Analysis
  • Genetic Predisposition
  • DNA-Binding Proteins
  • COS Cells
  • RNA Helicases
  • Single Nucleotide Polymorphism
  • Lymphatic Metastasis
  • DEAD-box RNA Helicases
  • Translocation
  • DDX6
  • Colorectal Cancer
  • Messenger RNA
  • Immunohistochemistry
  • Cancer Gene Expression Regulation
  • Genome
  • Polymerase Chain Reaction
  • MLL
  • Transcription Factors
  • Chromosome Aberrations
  • RTPCR
  • Up-Regulation
  • siRNA
  • Proto-Oncogene Proteins
  • Loss of Heterozygosity
  • Proto-Oncogene Protein c-ets-1
  • Neoplasm Proteins
  • MicroRNAs
  • Chromosome 11
  • Stomach Cancer
  • Sensitivity and Specificity
  • Western Blotting
  • Two-Hybrid System Techniques
  • FISH
  • KMT2A
  • DNA Copy Number Variations
  • Cytogenetic Analysis
  • Monocytes
  • Acute Myeloid Leukaemia
  • RNA Nucleotidyltransferases
Tag cloud generated 18 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DDX6 (cancer-related)

Rajgor D, Mellad JA, Soong D, et al.
Mammalian microtubule P-body dynamics are mediated by nesprin-1.
J Cell Biol. 2014; 205(4):457-75 [PubMed] Free Access to Full Article Related Publications
Nesprins are a multi-isomeric family of spectrin-repeat (SR) proteins, predominantly known as nuclear envelope scaffolds. However, isoforms that function beyond the nuclear envelope remain poorly examined. Here, we characterize p50(Nesp1), a 50-kD isoform that localizes to processing bodies (PBs), where it acts as a microtubule-associated protein capable of linking mRNP complexes to microtubules. Overexpression of dominant-negative p50(Nesp1) caused Rck/p54, but not GW182, displacement from microtubules, resulting in reduced PB movement and cross talk with stress granules (SGs). These cells disassembled canonical SGs induced by sodium arsenite, but not those induced by hydrogen peroxide, leading to cell death and revealing PB-microtubule attachment is required for hydrogen peroxide-induced SG anti-apoptotic functions. Furthermore, p50(Nesp1) was required for miRNA-mediated silencing and interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. These data identify p50(Nesp1) as a multi-functional PB component and microtubule scaffold necessary for RNA granule dynamics and provides evidence for PB and SG micro-heterogeneity.

Iio A, Takagi T, Miki K, et al.
DDX6 post-transcriptionally down-regulates miR-143/145 expression through host gene NCR143/145 in cancer cells.
Biochim Biophys Acta. 2013; 1829(10):1102-10 [PubMed] Related Publications
In various human malignancies, widespread dysregulation of microRNA (miRNA) expression is reported to occur and affects various cell growth programs. Recent studies suggest that the expression levels of miRNAs that act as tumor suppressors are frequently reduced in cancers because of chromosome deletions, epigenetical changes, aberrant transcription, and disturbances in miRNA processing. MiR-143 and -145 are well-recognized miRNAs that are highly expressed in several tissues, but down-regulated in most types of cancers. However, the mechanism of this down-regulation has not been investigated in detail. Here, we show that DEAD-box RNA helicase 6, DDX6 (p54/RCK), post-transcriptionally down-regulated miR-143/145 expression by prompting the degradation of its host gene product, NCR143/145 RNA. In human gastric cancer cell line MKN45, DDX6 protein was abundantly expressed and accumulated in processing bodies (P-bodies). DDX6 preferentially increased the instability of non-coding RNA, NCR143/145, which encompasses the miR-143/145 cluster, and down-regulated the expression of mature miR-143/145. In human monocytic cell line THP-1, lipopolysaccharide treatment promoted the assembly of P-bodies and down-regulated the expression of NCR143/145 and its miR-143/145 rapidly. In these cells, cycloheximide treatment led to a loss of P-bodies and to an increase in NCR143/145 RNA stability, thus resulting in up-regulation of miR-143/145 expression. These data demonstrate that DDX6 contributed to the control of NCR143/145 RNA stability in P-bodies and post-transcriptionally regulated miR-143/145 expression in cancer cells.

Schmid R, Meyer K, Spang R, et al.
Melanoma inhibitory activity promotes melanoma development through activation of YBX1.
Pigment Cell Melanoma Res. 2013; 26(5):685-96 [PubMed] Related Publications
Melanoma inhibitory activity (MIA), a small soluble secreted protein, is functionally important for progression of malignant melanoma. We recently revealed that p54(nrb) acts as a mediator of MIA action. In this study, we characterize the transcriptional regulation of p54(nrb) by MIA to explain MIA's molecular action. We identified one highly conserved region in the p54(nrb) promoter that is necessary and sufficient for MIA-dependent activation. Functional promoter analysis identified the transcription factor YBX1 as the mediator of MIA activation of p54(nrb) transcription. We screened the genome for further potential MIA-regulated genes carrying the element in their promoter regions. Integrating our sequence data with expression data from human melanomas identified a list of 23 potential MIA-YBX1 targets in melanomas. In summary, we present for the first time effects of MIA on transcriptional regulation. Uncovering new potential downstream effectors working via activation of YBX1 supports the important role of MIA in melanoma.

Bernhart E, Damm S, Wintersperger A, et al.
Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro.
Exp Cell Res. 2013; 319(13):2037-48 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-Jun(S73) phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment.

Stary S, Vinatzer U, Müllauer L, et al.
t(11;14)(q23;q32) involving IGH and DDX6 in nodal marginal zone lymphoma.
Genes Chromosomes Cancer. 2013; 52(1):33-43 [PubMed] Related Publications
Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell lymphoma that shares morphological and immunophenotypic characteristics with extranodal and splenic marginal zone lymphoma. Data on altered genes and signaling pathways are scarce in this rare tumor entity. To gain further insights into the genetic background of NMZL, seven cases were investigated by microarray analysis, G-banding, and FISH. Chromosomal imbalances were observed in 3/7 cases (43%) with gains of chromosome arms 1q, 8q, and 12q being the most frequent findings. Furthermore, we identified a translocation t(11;14)(q23;q32) involving IGH and DDX6. Chromosomal walking, expression analysis, siRNA-mediated gene knockdown and a yeast two hybrid screen were performed for further characterization of the translocation in vitro. In siRNA experiments, DDX6 appeared not to be involved in NF-κB activation as frequently observed for genes promoting lymphomagenesis but was found to interfere with the expression of BCL6 and BCL2 in an NF-κB independent manner. In conclusion, we identified several unbalanced aberrations and a t(11;14) involving IGH and DDX6 providing evidence for a contribution of DDX6 to lymphomagenesis by deregulation of BCL6 in NMZL.

Wang Y, Lui WY
Transforming growth factor-β1 attenuates junctional adhesion molecule-A and contributes to breast cancer cell invasion.
Eur J Cancer. 2012; 48(18):3475-87 [PubMed] Related Publications
Transforming growth factor-β1 (TGF-β1) is a potent regulator in promoting the invasion and proliferation of breast cancer cells. Junctional adhesion molecule-A (JAM-A) is a tight junction protein that displays an inverse relationship to cell invasiveness in breast cancer cells. Whether TGF-β1 signaling induces alteration of JAM-A expression leading to cell invasion has not been investigated. In this study, we report that TGF-β1 down-regulated JAM-A expression via its effect on both transcriptional and post-translational regulations of JAM-A, thus inducing cell invasion. On exploring whether TGF-β1 might be the upstream regulator of JAM-A expression, we found that knockdown of TGF-β receptors and canonical Smad signaling could upregulate JAM-A level and inhibit cell invasion in MDA-MB-231 cells. TGF-β1 treatment of MCF-7 cells caused a significant reduction of JAM-A mRNA and protein and induced cell invasion. Delineating the signal mechanisms involved in TGF-β1-mediated JAM-A repression, we found that TGF-β1 significantly inhibited JAM-A gene transcription via the activation of Smads. In addition to Smad activation, we found that involvement of p54 JNK is crucial for post-translational modification of TGF-β1-mediated JAM-A protein degradation. Blockage of JNK pathway by inhibitor could attenuate TGF-β1-induced cell invasion. We provide evidences for the first time that TGF-β1 induces breast cancer cell invasion via TGF-β1-mediated control on JAM-A expression. Identification of JAM-A as a downstream target of TGF-β1 represents a crucial mechanism in cancer progression.

Ward AM, Bidet K, Yinglin A, et al.
Quantitative mass spectrometry of DENV-2 RNA-interacting proteins reveals that the DEAD-box RNA helicase DDX6 binds the DB1 and DB2 3' UTR structures.
RNA Biol. 2011 Nov-Dec; 8(6):1173-86 [PubMed] Free Access to Full Article Related Publications
Dengue virus (DENV) is a rapidly re-emerging flavivirus that causes dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), diseases for which there are no available therapies or vaccines.  The DENV-2 positive-strand RNA genome contains 5' and 3' untranslated regions (UTRs) that have been shown to form secondary structures required for virus replication and interaction with host cell proteins.  In order to comprehensively identify host cell factors that bind the DENV-2 UTRs, we performed RNA chromatography, using the DENV-2 5' and 3' UTRs as "bait", combined with quantitative mass spectrometry.  We identified several proteins, including DDX6, G3BP1, G3BP2, Caprin1, and USP10, implicated in P body (PB) and stress granule (SG) function, and not previously known to bind DENV RNAs.  Indirect immunofluorescence microscopy showed these proteins to colocalize with the DENV replication complex.  Moreover, DDX6 knockdown resulted in reduced amounts of infectious particles and viral RNA in tissue culture supernatants following DENV infection. DDX6 interacted with DENV RNA in vivo during infection and in vitro this interaction was mediated by the DB1 and DB2 structures in the 3' UTR, possibly by formation of a pseudoknot structure.  Additional experiments demonstrate that, in contrast to DDX6, the SG proteins G3BP1, G3BP2, Caprin1 and USP10 bind to the variable region (VR) in the 3' UTR.  These results suggest that the DENV-2 3' UTR is a site for assembly of PB and SG proteins and, for DDX6, assembly on the 3' UTR is required for DENV replication.

Lachance DH, Yang P, Johnson DR, et al.
Associations of high-grade glioma with glioma risk alleles and histories of allergy and smoking.
Am J Epidemiol. 2011; 174(5):574-81 [PubMed] Free Access to Full Article Related Publications
Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility. Data from 855 high-grade glioma cases and 1,160 controls from 4 geographic regions of the United States during 1997-2008 were analyzed for interactions between allergy and smoking histories and inherited variants in 5 established glioma risk regions: 5p15.3 (TERT), 8q24.21 (CCDC26/MLZE), 9p21.3 (CDKN2B), 11q23.3 (PHLDB1/DDX6), and 20q13.3 (RTEL1). The inverse relation between allergy and glioma was stronger among those who did not (odds ratio(allergy-glioma) = 0.40, 95% confidence interval: 0.28, 0.58) versus those who did (odds ratio(allergy-glioma) = 0.76, 95% confidence interval: 0.59, 0.97; P(interaction) = 0.02) carry the 9p21.3 risk allele. However, the inverse association with allergy was stronger among those who carried (odds ratio(allergy-glioma) = 0.44, 95% confidence interval: 0.29, 0.68) versus those who did not carry (odds ratio(allergy-glioma) = 0.68, 95% confidence interval: 0.54, 0.86) the 20q13.3 glioma risk allele, but this interaction was not statistically significant (P = 0.14). No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. The authors' observations are consistent with a recent report that the inherited glioma risk variants in chromosome regions 9p21.3 and 20q13.3 may modify the inverse association of allergy and glioma.

Schiffner S, Zimara N, Schmid R, Bosserhoff AK
p54nrb is a new regulator of progression of malignant melanoma.
Carcinogenesis. 2011; 32(8):1176-82 [PubMed] Related Publications
Nuclear RNA-binding protein p54(nrb) and its murine homolog NonO are known to be involved in a variety of nuclear processes including transcription and RNA processing. Melanoma inhibitory activity (MIA) has been shown to play an essential role in the progression of malignant melanoma and to influence melanoma-associated molecules and pathways in the early tumor formation steps. Interestingly, recent studies suggest that MIA is a regulator of p54(nrb). Here, we show that p54(nrb) is strongly expressed and localized in the nucleus of both melanoma cell lines and melanoma tissue samples compared with normal human melanocytes or normal skin, respectively. Furthermore, all tested melanoma cell lines revealed strong p54(nrb) promoter activity. Treatment with MIA-specific small interfering RNAs showed an influence of MIA on p54(nrb) expression on both messenger RNA (mRNA) and protein level. Knockdown of p54(nrb) protein in melanoma cell lines led to reduced proliferation rates and to a strong decrease in their migratory potential. In addition, attachment to laminin and poly-l-lysine was significantly increased. We could identify Connexin-43 (Cx-43) as a downstream target molecule of p54(nrb) as knockdown of p54(nrb) resulted in enhanced Cx-43 mRNA and protein levels. As a confirmation of these findings, melanoma cell lines showed very low Cx-43 expression levels compared with melanocytes. Our results demonstrate that p54(nrb) is highly expressed in malignant melanoma and, as a MIA target molecule, it seems to be involved in the development and progression of malignant melanoma.

Desouki MM, Liao S, Conroy J, et al.
The genomic relationship between primary breast carcinomas and their nodal metastases.
Cancer Invest. 2011; 29(4):300-7 [PubMed] Related Publications
We screened the whole tumor genome to identify DNA copy number gains and losses that discriminate between primary breast carcinomas (MP) and their nodal metastases (ML). Six candidate genes were confirmed by quantitative PCR to have differentially distributed copy number changes. Three of the genes (ERRγ, DDX6, and TIAM1) were more commonly amplified in nodal metastases. Principal component analysis revealed that MP-ML pairs varied markedly in their genomic divergence. The latter was larger in PR-negative tumors. Nodal metastases may form early or late in the development of breast carcinomas and PR-negative tumors may metastasize earlier or are genomically less stable.

Radeva M, Hofmann T, Altenberg B, et al.
The database dbEST correctly predicts gene expression in colon cancer patients.
Curr Pharm Biotechnol. 2008; 9(6):510-5 [PubMed] Related Publications
This study aims to test the predictive power of gene expression data derived from NIH's database dbEST, which collects gene expression results from a large number and variety of DNA array experiments. The motivation of this study is to make comparable experimental studies, which are usually performed only for one or a few tissues or organs, with a wide variety of other tissues. Confirmation of a good predictive power of dbEST would put a number of interesting and partially surprising recent findings, solely based on data mining, on a more solid basis than available so far. The expression of nine genes (eIF4E, DDX6, HAT1, USP28, HSP90(beta, PKM2, PLK1, COX2 and OPN) plus two calibration genes in paired normal and cancer colon tissues of eight individual patients was investigated by quantitative RT-PCR and compared with the predictions made by the data-base. GUS and beta-actin reveal only little variation among different patients, making them good internal calibration standards. In normal colon tissue, data mining correctly predicts the expression of all nine genes, which covers two orders of magnitude. In cancer, dbEST is somewhat less precise, but still valuable for the comparison with clinical results.

Lin F, Wang R, Shen JJ, et al.
Knockdown of RCK/p54 expression by RNAi inhibits proliferation of human colorectal cancer cells in vitro and in vivo.
Cancer Biol Ther. 2008; 7(10):1669-76 [PubMed] Related Publications
Colorectal cancer is the third most common cancer in both men and women around the world. Although much progress of the mechanism of colorectal carcinogenesis has been made, the studies centering on the mechanisms of tumorigenesis are much needed to be further exploited. The overexpression of RCK/p54 gene, a member of the DEAD box protein/RNA helicase family, has been found in this malignancy. Roles of RCK in the development of colon cancer, however, are unknown. In this report, we explored whether RCK/p54 plays a role in maintaining the malignant phenotype and functions in the canonical Wnt signaling pathway of colorectal cancer cells harboring an APC mutation. The ectopic overexpression of RCK/p54 gene in colorectal cancer cells by transfection with RCK/p54 cDNA could lead to a significant increase of Tcf transcriptional activity and expression levels of Wnt target genes. By RNAi assay, we also observed that the Tcf transcriptional activity in LoVo-shRNA cells was significantly decreased by approximately 61.3%, while the mRNA and protein expression levels of Wnt target genes were also obviously decreased. Furthermore, the anti-tumour effects and its possible mechanisms of actions in LoVo cells elicited by a decrease in the level of RCK/p54 by RNAi were examined. Results showed that RCK/p54 downregulation could significantly reduce the viability of LoVo cells, increased cell number of S phase, led to cell apoptosis induction, and inhibited tumor growth in nude mice. Taken together, RCK/ p54 might be a determinant of colorectal cancer proliferation by activating the canonical Wnt pathway and RCK/p54-shRNA might be a potential strategy for colorectal cancer gene therapy.

Mrózek K
Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype.
Semin Oncol. 2008; 35(4):365-77 [PubMed] Free Access to Full Article Related Publications
Patients with acute myeloid leukemia (AML) harboring three or more acquired chromosome aberrations in the absence of the prognostically favorable t(8;21)(q22;q22), inv(16)(p13q22)/t(6;16)(p13;q22), and t(15;17)(q22;q21) aberrations form a separate category - AML with a complex karyotype. They constitute 10% to 12% of all AML patents, with the incidence of complex karyotypes increasing with the more advanced age. Recent studies using molecular-cytogenetic techniques (spectral karyotyping [SKY], multiplex fluorescence in situ hybridization [M-FISH]) and array comparative genomic hybridization (a-CGH) considerably improved characterization of previously unidentified, partially identified, or cryptic chromosome aberrations, and allowed precise delineation of genomic imbalances. The emerging nonrandom pattern of abnormalities includes relative paucity, but not absence, of balanced rearrangements (translocations, insertions, or inversions), predominance of aberrations leading to loss of chromosome material (monosomies, deletions, and unbalanced translocations) that involve, in decreasing order, chromosome arms 5q, 17p, 7q, 18q, 16q, 17q, 12p, 20q, 18p, and 3p, and the presence of recurrent, albeit less frequent and often hidden (in marker chromosomes and unbalanced translocations) aberrations leading to overrepresentation of segments from 8q, 11q, 21q, 22q, 1p, 9p, and 13q. Several candidate genes have been identified as targets of genomic losses, for example, TP53, CTNNA1, NF1, ETV6, and TCF4, and amplifications, for example, ERG, ETS2, APP, ETS1, FLI1, MLL, DDX6, GAB2, MYC, TRIB1, and CDX2. Treatment outcomes of complex karyotype patients receiving chemotherapy are very poor. They can be improved to some extent by allogeneic stem cell transplantation in younger patients. It is hoped that better understanding of genomic alterations will result in identification of novel therapeutic targets and improved prognosis in patients with complex karyotypes.

Cannon GM, Balasudramani M, Getzenberg RH
Characterization of nuclear matrix protein alterations associated with renal cell carcinoma.
Urology. 2007; 69(6):1227-30 [PubMed] Related Publications
OBJECTIVES: Nuclear matrix proteins (NMPs), which constitute the nuclear skeleton, play a role in regulating gene expression and are thought to play an important role in carcinogenesis. Five NMPs specific to renal cell carcinoma (RCC) have been previously identified, RCCA 1 to 5. Our aim was to identify the sequence of these novel NMPs that are associated with RCC.
METHODS: NMPs were extracted from five conventional clear cell RCC specimens from patients undergoing surgical excision for presumed RCC. The RCCA proteins identified were analyzed by matrix-assisted light desorption ionization mass spectrometry to determine their peptide mass fingerprint. This fingerprint was then analyzed by searching the Mascot and National Institutes of Health BLAST (basic local alignment search tool) databases to determine protein identification.
RESULTS: Only RCCA-1 and RCCA-2 were able to be consistently identified from each tumor specimen by the reverse staining method necessary to perform mass spectrometry. Mass spectrometry peptide mass fingerprinting revealed that RCCA-1 appears to be a differentially spliced form of nucleoporin p54 that has been identified in endometrial carcinoma. RCCA-2 was identified as an albumin-like protein.
CONCLUSIONS: This is the first report of nucleoporin p54 and albumin alterations in RCC. The identification of an abnormal nucleoporin in RCC suggests that alterations in nuclear transport might play a role in the development of this disease. The alterations in these NMPs suggest future areas for investigation in identifying diagnostic markers of, or therapeutic targets for, RCC.

Poppe B, De Paepe A, Speleman F
Acquired chromosomal rearrangements targeting selected transcription factors: contribution of molecular cytogenetic and expression analyses to the identification of clinically and biologically relevant subgroups in hematological malignancies.
Verh K Acad Geneeskd Belg. 2007; 69(1):47-64 [PubMed] Related Publications
In leukemias chromosomal aberrations, balanced translocations in particular, play a critical role in the oncogenic process. The characterization of these chromosomal alterations was crucial to the discovery of the genes implicated in leukemogenesis, as the chromosomal breakpoints indicated their genomic localization. In addition, these molecular defects may serve as targets for diagnostic essays and can have a major prognostic value. Finally, the characterization of the deregulated cellular pathways potentially identifies targets for therapeutic intervention. In this paper we summarize our efforts to expand the current knowledge of the diagnostic, prognostic or biological significance of selected chromosomal aberrations identified in M-FISH studies. First, we illustrated the power of M-FISH in dissecting complex chromosomal aberrations in myeloid neoplasms. MLL amplification was defined as a clinical entity characterized by adverse prognosis and within the multitude and variety of chromosomal rearrangements a pattern of a limited number of cytogenetic subclasses was discerned. In leukemias characterized by 11q23 amplification, we described the amplicon and confirmed MLL, in addition to DDX6, as a principal amplification target. Molecular characterization of a large series of unselected sporadic and recurrent 3q26 rearranged leukemias confirmed the decisive role of ectopic EVI1 expression in these malignancies. We contributed to an extensive analysis of the phenotypical and prognostic features of T-ALL characterized by HOX11L2 expression and identified HOX11L2 overexpression as one of the most frequent genetic defects in childhood T-ALL, associated with intermediate prognosis. Finally, we designed and validated diagnostic tools for the detection of the t(9;14) (p13;q34) resulting in PAX5 overexpression and convincingly associated the presence of this rearrangement to high-grade morphology and karyotype complexity. In conclusion, the series of investigations presented here clearly illustrate the benefits of M-FISH as molecular tool for the dissection and characterization of complex and cryptic rearrangements. The subsequent reports demonstrate the utility of molecular cytogenetics and expression analyses to the clinical management of patients diagnosed with hematological malignancies.

Hisada-Ishii S, Ebihara M, Kobayashi N, Kitagawa Y
Bipartite nuclear localization signal of matrin 3 is essential for vertebrate cells.
Biochem Biophys Res Commun. 2007; 354(1):72-6 [PubMed] Related Publications
Matrin 3, a nuclear matrix protein has potential (1) to withhold promiscuously edited RNAs within the nucleus in cooperation with p54(nrb) and PSF, (2) to mediate NMDA-induced neuronal death, and (3) to modulate promoter activity of genes proximal to matrix/scaffold attachment region (MAR/SAR). We identified a bipartite nuclear localization signal (NLS) of chicken matrin 3 (cmatr3) at residues 583-602. By expressing green fluorescent protein (GFP) fused to the NLS mutant in chicken DT40 cells, we showed an essential role of the NLS for cell proliferation. Furthermore, we showed that both clusters of basic amino acids and a linker of the bipartite NLS were essential and sufficient for the nuclear import of GFP. Exogenous cmatr3 rescued the HeLa cells where human matrin 3 was suppressed by RNA interference, but cmatr3 containing deletions at either of the basic amino acid clusters or the linker could not.

Terenzi F, Hui DJ, Merrick WC, Sen GC
Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56.
J Biol Chem. 2006; 281(45):34064-71 [PubMed] Related Publications
Human P54 and P56 proteins are tetratricopeptide proteins that are encoded by two closely related genes, ISG54 and ISG56. These genes are induced strongly but transiently when cells are treated with interferons or double-stranded RNA or infected with a variety of viruses. We observed that, although double-stranded RNA or Sendai virus infection induced the two genes with similar kinetics, their induction kinetics in response to interferon-beta were quite different. The induction kinetics by virus infection were also different between two cell lines. Functionally the two proteins were similar. Like P56, P54 bound to the translation initiation factor eIF3 and inhibited translation. However, unlike P56, P54 bound to both the "e" and the "c" subunits of eIF3. Consequently, P54 inhibited two functions of eIF3. Like P56, it inhibited the ability of eIF3 to stabilize the eIF2 x GTP x Met-tRNA(i) ternary complex. But in addition, it also inhibited the formation of the 48 S pre-initiation complex between the 40 S ribosomal subunit and the 20 S complex composed of eIF3, ternary complex, eIF4F, and mRNA. Thus, although similar in structure, the human P54 and P56 proteins are induced differently and function differently.

Akao Y, Matsumoto K, Ohguchi K, et al.
Human DEAD-box/RNA unwindase rck/p54 contributes to maintenance of cell growth by affecting cell cycle in cultured cells.
Int J Oncol. 2006; 29(1):41-8 [PubMed] Related Publications
Understanding the control of gene expression in cancer cells requires defining the molecular and cellular basis of RNA metabolism compared with that in steady-state normal cells. Previously, we reported evidence that human RNA structure-modifying unwindase rck/p54, a member of the DEAD-box family, was highly expressed in most of the malignant cell lines tested and that this expression was linked to malignant transformation. Here, we show that rck/p54 positively affects cell growth, probably by modulating the gene expression at the translational level in cultured cells. In cell growth and differentiation induced by external stimuli, the level of rck/p54 expression was up-regulated during cell proliferation and down-regulated during differentiation. The down-regulation of rck/p54 in HeLa cells by RNAi induced cell growth inhibition through cell cycle arrest at S phase. Immunoprecipitation using anti-rck/p54 antibody in HeLa cells demonstrated the co-precipitation of rck/p54 with eIF4E, which is well-known to bind to the 5'cap-structure, resulting in initiation of translation. These data suggest that rck/p54 contributes to cell growth possibly by modulating translation-initiation control of the genes involved in the cell proliferation, which is a newly defined mechanism leading to carcinogenesis.

Buggy Y, Maguire TM, McDermott E, et al.
Ets2 transcription factor in normal and neoplastic human breast tissue.
Eur J Cancer. 2006; 42(4):485-91 [PubMed] Related Publications
The Ets family of transcription factors regulate the expression of multiple genes involved in tumour formation and progression. The aim of this work was to test the hypothesis that the expression of Ets2 in breast cancers was associated with parameters of tumour progression and metastasis. Using reverse-transcriptase polymerase chain reaction (RT-PCR), Ets2 mRNA was detected in 69% of 181 breast carcinomas, 63% of 43 fibroadenomas and 47% of 43 specimens of normal breast tissue. Levels were significantly higher in carcinomas compared with normal breast tissue (P = 0.006). Using Western blotting, Ets2 protein was found to migrate as two bands with molecular masses of 52 kDa (p52) and 54kDa (p54). Levels of both proteins were significantly higher in the carcinomas compared with both fibroadenomas (P = 0.0001) and normal breast tissue (P = 0.0001). In the carcinomas, a significant relationship was found between the p52 and p54 form of Ets2 (r = 0.51, P < 0.0001; Spearman correlation). Also, in the carcinomas, a significant correlation was found between both forms of Ets2 protein and urokinase plasminogen activator (uPA) (for p52, r = 0.43, P = 0.0005, n = 68; for p54, r = 0.50, P = 0.0001, n = 68). As Ets2 binding sites are present on the uPA promoter, Ets2 may be one of the transcription factors regulating uPA expression in human breast cancer.

Malathi K, Paranjape JM, Bulanova E, et al.
A transcriptional signaling pathway in the IFN system mediated by 2'-5'-oligoadenylate activation of RNase L.
Proc Natl Acad Sci U S A. 2005; 102(41):14533-8 [PubMed] Free Access to Full Article Related Publications
Virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins, such as 2'-5' oligoadenylate synthetases. 2'-5' oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNase L. Although RNase L is required for a complete IFN antiviral response and mutations in the RNase L gene (RNASEL or HPC1) increase prostate cancer rates, it is unknown how 2-5A affects these biological endpoints through its receptor, RNase L. Presently, we show that 2-5A activation of RNase L produces a remarkable stimulation of transcription (>/=20-fold) for genes that suppress virus replication and prostate cancer. Unexpectedly, exposure of DU145 prostate cancer cells to physiologic levels of 2-5A (0.1 muM) induced approximately twice as many RNA species as it down-regulated. Among the 2-5A-induced genes are several IFN-stimulated genes, including IFN-inducible transcript 1/P56, IFN-inducible transcript 2/P54, IL-8, and IFN-stimulated gene 15. 2-5A also potently elevated RNA for macrophage inhibitory cytokine-1/nonsteroidal antiinflammatory drug-activated gene-1, a TGF-beta superfamily member implicated as an apoptotic suppressor of prostate cancer. Transcriptional signaling to the macrophage inhibitory cytokine-1/nonsteroidal antiinflammatory drug-activated gene-1 promoter by 2-5A was deficient in HeLa cells expressing a nuclease-dead mutant of RNase L and was dependent on the mitogen-activated protein kinases c-Jun N-terminal kinase and extracellular signal-regulated kinase, both of which were activated in response to 2-5A treatments. Because 2-5A and RNase L participate in defenses against viral infections and prostate cancer, our findings have implications for basic cellular mechanisms that control major pathogenic processes.

Poppe B, Vandesompele J, Schoch C, et al.
Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies.
Blood. 2004; 103(1):229-35 [PubMed] Related Publications
MLL amplification was recently recognized as a recurrent aberration in acute myeloid leukemia (AML) and myelodys-plastic syndrome (MDS), associated with adverse prognosis and karyotype complexity. Here we present detailed results of fluorescence in situ hybridization (FISH) and expression analyses of MLL and 5 selected 11q candidate oncogenes (CBL, DDX6, ETS1, FLI1, and PLZF) in 31 patient samples and one cell line with 11q23 gain. FISH analyses revealed that the 11q23 amplicon invariably encompassed MLL, DDX6, ETS1, and FLI1, whereas expression analyses identified MLL and DDX6 as the most differentially expressed genes among samples with and without 11q23 copy gain or amplification. In MLL-amplified samples, a significant transcriptional up-regulation of MEIS1, PROML1, ADAM10, NKG2D, and ITPA was noted. Further analyses, designed to elucidate a possible role of the 11q overexpressed genes (MLL, DDX6, FLI1, and ETS1) in unselected MDS and AML samples, revealed a significant upregulation of MLL in MDS. Our findings confirm the MLL gene as a prominent target of 11q23 amplification and provide further evidence for an etiologic role for MLL gain of function in myeloid malignancies. In addition, our results indicate that the transcriptional program associated with MLL rearrangements and MLL overexpression displays significant similarities.

Miyaji K, Nakagawa Y, Matsumoto K, et al.
Overexpression of a DEAD box/RNA helicase protein, rck/p54, in human hepatocytes from patients with hepatitis C virus-related chronic hepatitis and its implication in hepatocellular carcinogenesis.
J Viral Hepat. 2003; 10(4):241-8 [PubMed] Related Publications
Hepatitis C virus (HCV) infection is the most common cause of chronic hepatitis, which frequently progresses to hepatocellular carcinoma. The pathogenesis of its persistent infection and tumour progression has not been fully characterized yet. The RCK gene was previously cloned at the breakpoint of the t(11;14)(q23;q32) chromosome translocation observed in human B-cell lymphoma cell line RC-K8. The RCK protein, rck/p54, which is a 54-kDa cytoplasmic protein belonging to the DEAD box/RNA helicase family, is considered to facilitate the translation of mRNA(s) of genes for cell proliferation and malignant transformation not only in B-cell lymphomas having the t(11;14) translocation but also in other solid tumours. The aim of this work was to examine the involvement of rck/p54 in carcinogenesis of hepatocellular carcinoma from HCV-related chronic hepatitis. We examined the expression of rck/p54 in 29 cases of HCV-related chronic hepatitis and eight cases of hepatocellular carcinoma by immunohistochemistry and Western blot analysis. Twenty-six of 29 cases with HCV-related chronic hepatitis and all cases with hepatocellular carcinoma tested overexpressed rck/p54 protein. The expression of rck/p54 was lowered by treatment with IFN-alpha in two cases who showed the decrease in HCV RNA levels. These findings suggest that rck/p54 protein is possibly involved in the replication of HCV genomes in hepatocytes and in tumourigenesis of hepatocellular carcinomas.

Luciano F, Herrant M, Jacquel A, et al.
The p54 cleaved form of the tyrosine kinase Lyn generated by caspases during BCR-induced cell death in B lymphoma acts as a negative regulator of apoptosis.
FASEB J. 2003; 17(6):711-3 [PubMed] Related Publications
Engagement of the B cell receptor antigen (BCR) triggers apoptosis on immature B cell lines. We report here that BCR triggering leads to caspase activation followed by Lyn cleavage and induction of apoptosis. The cleavage process is mitochondrion-dependent and involves caspases 9 and 7. Stable expression of the cleaved form of Lyn (Lyn-Delta-N) in Ramos B cells impairs BCR-mediated apoptosis as judged by loss of Delta(psi)m, caspase activation and PARP cleavage. Activation of the main survival pathways upon BCR-triggering was unaltered in both cell variants. However, the PI3-K inhibitor Ly294002 resensitizes Lyn-Delta-N cells to apoptosis. Selected cDNA expression arrays revealed that anti-IgM modulates the expression of approximately 20 genes in both cell variants. Among them, only c-Myc was found to be differentially regulated, which suggests a role for c-Myc in the B cell apoptotic response. Interestingly, c-Myc expression decreased more rapidly in Lyn-Delta-N compared with Lyn-WT cells during the first hours of anti-IgM stimulation. Nevertheless, rapid down-regulation of c-Myc following BCR engagement seems to correlate with the resistance of B cells to apoptosis. Thus, the soluble form of Lyn generated by caspases following BCR triggering acts as an inhibitor of B lymphocyte death likely through the modulation of c-Myc expression.

Shav-Tal Y, Zipori D
PSF and p54(nrb)/NonO--multi-functional nuclear proteins.
FEBS Lett. 2002; 531(2):109-14 [PubMed] Related Publications
Proteins are often referred to in accordance with the activity with which they were first associated or the organelle in which they were initially identified. However, a variety of nuclear factors act in multiple molecular reactions occurring simultaneously within the nucleus. This review describes the functions of the nuclear factors PSF (polypyrimidine tract-binding protein-associated splicing factor) and p54(nrb)/NonO. PSF was initially termed a splicing factor due to its association with the second step of pre-mRNA splicing while p54(nrb)/NonO was thought to participate in transcriptional regulation. Recent evidence shows that the simplistic categorization of PSF and its homolog p54(nrb)/NonO to any single nuclear activity is not possible and in fact these proteins exhibit multi-functional characteristics in a variety of nuclear processes.

Cook RD, Hodgson TA, Molyneux EM, et al.
Tracking familial transmission of Kaposi's sarcoma-associated herpesvirus using restriction fragment length polymorphism analysis of latent nuclear antigen.
J Virol Methods. 2002; 105(2):297-303 [PubMed] Related Publications
Intra-familial transmission of Kaposi's sarcoma associated herpesvirus (KSHV) is likely to occur in geographical regions where KSHV infection is highly endemic. Transmission has been studied previously indirectly using serological techniques, however direct documentation of specific transmission routes has yet to be reported. The internal repeat domain (IRD) of the KSHV opening reading frame (ORF) 73 was shown previously to exhibit restriction-fragment length polymorphism (RFLP). Analysis of such polymorphism was undertaken using nested ORF 73 IRD PCR products derived from the blood and mouth rinse samples of individuals in Malawian family groups. The resulting RFLP patterns were unique to an individual and could be compared between family members. In three of eight families studied, identical RFLP patterns were recovered from family members; in the remaining five families, dissimilar RFLP patterns were revealed. Results from RFLP analysis were compared to sequencing data recovered from family members for the first variable region of the hypervariable KSHV ORF K1. Patterns of intra- and extra-familial transmission inferred from ORF K1 sequencing data were corroborated mainly using ORF 73 IRD RFLP analysis.

Hashimoto K, Nakagawa Y, Morikawa H, et al.
Co-overexpression of DEAD box protein rck/p54 and c-myc protein in human colorectal adenomas and the relevance of their expression in cultured cell lines.
Carcinogenesis. 2001; 22(12):1965-70 [PubMed] Related Publications
The RCK gene was cloned through a study of the breakpoint of the t(11;14)(q23;q32) chromosomal translocation observed in a human B-cell lymphoma and overexpression of the protein (rck/p54) due to the translocation was shown to be associated with malignant transformation. The rck/p54 protein belongs to the DEAD box protein/RNA helicase family, which has a variety of functions such as translation initiation, pre-mRNA splicing and ribosome assembly. It is considered that rck/p54 protein may have significant effects on the mRNA structure of genes associated with cell proliferation, facilitating protein synthesis. Expression of rck/p54 in colorectal adenomas, which are a premalignant lesion of colorectal cancer, was examined by Western blot analysis and immunohistochemistry. The rck/p54 protein was found to be overexpressed in tumor tissues resected from 17 of 26 cases (65.4%) of colorectal adenomas and 13 of 14 c-myc-positive cases (92.8%) also co-overexpressed rck/p54 protein. Thus, a significant correlation between rck/p54 and c-myc co-overexpression was found (Spearman's rank correlation, P = 0.0018). We demonstrate that overexpression of rck/p54 in two different cell lines, COS 7 and human colorectal cancer cell line SW480, caused an increase in c-myc protein levels by enhancement of its translation efficiency and/or stabilization of its mRNA. These results suggest that rck/p54 of the DEAD box protein/RNA helicase family may contribute to cell proliferation and carcinogenesis in the development of human colorectal tumors at the translational level by increasing synthesis of c-myc protein.

Roth JA, Swisher SG, Meyn RE
p53 tumor suppressor gene therapy for cancer.
Oncology (Williston Park). 1999; 13(10 Suppl 5):148-54 [PubMed] Related Publications
Gene therapy has the potential to provide cancer treatments based on novel mechanisms of action with potentially low toxicities. This therapy may provide more effective control of locoregional recurrence in diseases like non-small-cell lung cancer (NSCLC) as well as systemic control of micrometastases. Despite current limitations, retroviral and adenoviral vectors can, in certain circumstances, provide an effective means of delivering therapeutic genes to tumor cells. Although multiple genes are involved in carcinogenesis, mutations of the p53 gene are the most frequent abnormality identified in human tumors. Preclinical studies both in vitro and in vivo have shown that restoring p53 function can induce apoptosis in cancer cells. High levels of p53 expression and DNA-damaging agents like cisplatin (Platinol) and ionizing radiation work synergistically to induce apoptosis in cancer cells. Phase I clinical trials now show that p53 gene replacement therapy using both retroviral and adenoviral vectors is feasible and safe. In addition, p53 gene replacement therapy induces tumor regression in patients with advanced NSCLC and in those with recurrent head and neck cancer. This article describes various gene therapy strategies under investigation, reviews preclinical data that provide a rationale for the gene replacement approach, and discusses the clinical trial data available to date.

Nakagawa Y, Morikawa H, Hirata I, et al.
Overexpression of rck/p54, a DEAD box protein, in human colorectal tumours.
Br J Cancer. 1999; 80(5-6):914-7 [PubMed] Free Access to Full Article Related Publications
The RCK gene is a target of the t(11;14)(q23;q32) chromosomal translocation observed in human B-cell lymphoma, and the overexpression of its protein (rck/p54) by the translocation was shown to cause malignant transformation. The rck/p54 protein belongs to the DEAD box protein/RNA helicase family, which has a variety of functions such as translation initiation, pre-mRNA splicing and ribosome assembly. The expression of rck p54 in colorectal adenocarcinoma cells was examined by immunohistochemistry and Western blot analysis. The rck/p54 protein was found to be overexpressed in tumour tissues resected from 13 (50%) out of 26 cases of colorectal adenocarcinomas and two out of two (100%) cases of colonic severe dysplastic adenomas. In view of activities of rck/p54 determined in other tissue types, we suggest that rck/p54 may contribute to the cell proliferation and carcinogenesis at the translational level in the development of colorectal tumours.

Akiyama K, Akao Y, Yokoyama M, et al.
Expression of two dead box genes (DDX1 and DDX6) is independent of that of MYCN in human neuroblastoma cell lines.
Biochem Mol Biol Int. 1999; 47(4):563-8 [PubMed] Related Publications
To examine whether two DEAD box genes, DDX1 and DDX6, would have some roles in the progression of tumors, we investigated the correlation of the expression of these genes with that of MYCN in neuroblastomas either with or without MYCN amplification. The mRNA of MYCN was observed only in the cell lines with amplification of MYCN. The mRNAs of DDX1 and DDX6 were found in all the cell lines examined, but the correlation between the mRNA levels of DDX1 or DDX6 and MYCN was poor. These findings suggest that the expression of neither DEAD box gene is correlated with the gene expression of MYCN.

Kaul D, Kaur M
LDL-dependent regulation of Bcl-2 and cyclin 'D' gene expression in lymphocytes from normal and CML patients.
Cancer Lett. 1997; 119(2):131-5 [PubMed] Related Publications
Effect of low-density lipoprotein (LDL) on the expression of Bcl-2 as well as cyclin 'D' genes was studied in Receptor 'Ck' (+ve) and Receptor 'Ck'(-ve) human lymphocytes. LDL had no effect upon the elevated levels of Bcl-2 and cyclin 'D' gene products in Receptor 'Ck' (-ve) lymphocytes (from untreated CML patients), whereas in Receptor 'Ck' (+ve) lymphocytes (from normal subjects), the exposure to LDL regulated the level of cyclin 'D' gene product without initiating the expression of bcl-2 gene product. However, blockage of Receptor 'Ck' in normal lymphocytes, through its specific antibody (Ab-RCk) in presence or absence of LDL, resulted in the induction of both cyclin 'D' (at 4 h interval) and bcl-2 (at 12 h interval) gene products. Based upon these results, we propose that Receptor 'Ck' deficiency in cells may inherit defective apoptosis and capacity proliferation leading to leukemic transformation.

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