Publications
76 results found
Hu Y, Li S, Yang M, et al., 2014, Sorcin silencing inhibits epithelial-to-mesenchymal transition and suppresses breast cancer metastasis in vivo, Breast Cancer Research and Treatment, Vol: 143, Pages: 287-299, ISSN: 0167-6806
Sorcin, a 22-kDa calcium-binding protein, renders cancer cells resistant to chemotherapeutic agents, thus playing an important role in multidrug resistance. As there is a clear association between drug resistance and an aggressive phenotype, we asked whether sorcin affects also the motility, invasion, and stem cell characteristics of cancer cells. We have used both RNA interference (transient and stable expression of hairpins) and a lentiviral expression vector to experimentally modulate sorcin expression in a variety of cells. We demonstrate that sorcin depletion in MDA-MB-231 breast cancer cells reduces the pool of CD44+/CD24− and ALDH1high cancer stem cells (CSCs) as well as mammosphere-forming capacity. We also observe that sorcin regulates epithelial-mesenchymal transition and CSCs partly through E-cadherin and vascular endothelial growth factor expression. This leads to the acquisition of an epithelial-like phenotype, attenuating epithelial-mesenchymal transition and suppression of metastases in nude mice. The sorcin-depleted phenotype can also be reproduced in lung adenocarcinoma A549 cells and lung fibrosarcoma HT1080 cells. In addition, overexpression of sorcin in MCF7 cells, which have low endogenous sorcin expression levels, increases their migration and invasion in vitro. This offers the rationale for the development of therapeutic strategies down-regulating sorcin expression for the treatment of cancer.
Khongkow P, Karunarathna U, Khongkow M, et al., 2013, FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance, Oncogene, Vol: 33, Pages: 4144-4155, ISSN: 1476-5594
FOXM1 is implicated in genotoxic drug resistance but its mechanism of action remains elusive. We show here that FOXM1-depletion can sensitize breast cancer cells and mouse embryonic fibroblasts (MEFs) into entering epirubicin-induced senescence, with the loss of long-term cell proliferation ability, the accumulation of γH2AX foci, and the induction of senescence-associated β-galactosidase activity and cell morphology. Conversely, reconstitution of FOXM1 in FOXM1-deficient MEFs alleviates the accumulation of senescence-associated γH2AX foci. We also demonstrate that FOXM1 regulates NBS1 at the transcriptional level through an forkhead response element on its promoter. Like FOXM1, NBS1 is overexpressed in the epirubicin-resistant MCF-7EpiR cells and its expression level is low but inducible by epirubicin in MCF-7 cells. Consistently, overexpression of FOXM1 augmented and FOXM1 depletion reduced NBS1 expression and epirubicin-induced ataxia-telangiectasia mutated (ATM)phosphorylation in breast cancer cells. Together these findings suggest that FOXM1 increases NBS1 expression and ATM phosphorylation, possibly through increasing the levels of the MRN(MRE11/RAD50/NBS1) complex. Consistent with this idea, the loss of P-ATM induction by epirubicin in the NBS1-deficient NBS1-LBI fibroblasts can be rescued by NBS1 reconstitution. Resembling FOXM1, NBS1 depletion also rendered MCF-7 and MCF-7EpiR cells more sensitive to epirubicin-induced cellular senescence. In agreement, the DNA repair-defective and senescence phenotypes in FOXM1-deficent cells can be effectively rescued by overexpression of NBS1. Moreover, overexpression of NBS1 and FOXM1 similarly enhanced and their depletion downregulated homologous recombination (HR) DNA repair activity. Crucially, overexpression of FOXM1 failed to augment HR activity in the background of NBS1 depletion, demonstrating that NBS1 is indispensable for the HR function of FOXM1. The physiological relevance of the regulation o
Khongkow M, Olmos Y, Gong C, et al., 2013, SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer, CARCINOGENESIS, Vol: 34, Pages: 1476-1486, ISSN: 0143-3334
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- Citations: 121
Raguz S, Adams C, Masrour N, et al., 2013, Loss of O-6-methylguanine-DNA methyltransferase confers collateral sensitivity to carmustine in topoisomerase II-mediated doxorubicin resistant triple negative breast cancer cells, Biochemical Pharmacology, Vol: 85, Pages: 186-196, ISSN: 0006-2952
Triple-negative breast cancer is characterized by aggressive tumours whose cells lack oestrogen and progesterone receptors and do not over-express HER2. It accounts for approximately 10–15% of breast cancer cases. We sought to generate a cellular model of chemotherapy drug resistance for this type of disease to provide the tools for the development of new therapies. Doxorubicin is a component of some chemotherapy regimes used to treat this form of cancer but resistance preventing disease eradication frequently occurs, mainly due to over-expression of drug transporters such as P-glycoprotein. CALDOX cells were generated by exposure of CAL51 to doxorubicin. Resistance to doxorubicin did not involve drug transporters, as the both parental and resistant cells accumulated doxorubicin to comparable levels. CALDOX cells had slower proliferation rate and an extended G1 cell cycle stage than the parental line, mainly due to an intrinsic activation of CDNK1 (p21), but this cell cycle block was not involved in the mechanism of resistance. CALDOX cells had reduced levels of TOP2A (topoisomerase IIα) and were cross resistant to the topoisomerase II inhibitors etoposide and mitoxantrone. CALDOX cells showed collateral sensitivity to carmustine due to the lack of O6-methylguanine-DNA-methyltransferase (MGMT) expression, related to the hypermethylation of its promoter. The collateral sensitivity of CALDOX cells to carmustine provides the rationale to evaluate MGMT promoter methylation status to design better therapeutic strategies for triple negative breast cancer.
Lombardo Y, Filipovic A, Molyneux G, et al., 2012, Nicastrin regulates breast cancer stem cell properties and tumor growth in vitro and in vivo, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 16558-16563, ISSN: 0027-8424
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- Citations: 60
Payne RE, Wang F, Su N, et al., 2012, Viable circulating tumour cell detection using multiplex RNA <i>in situ</i> hybridisation predicts progression-free survival in metastatic breast cancer patients, BRITISH JOURNAL OF CANCER, Vol: 106, Pages: 1790-1797, ISSN: 0007-0920
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- Citations: 48
Payne RE, Hava NL, Page K, et al., 2012, The presence of disseminated tumour cells in the bone marrow is inversely related to circulating free DNA in plasma in breast cancer dormancy, British Journal of Cancer, Vol: 106, Pages: 375-382, ISSN: 0007-0920
Background:The aim of this study was to gain insight into breast cancer dormancy by examining different measures of minimal residual disease (MRD) over time in relation to known prognostic factors.Methods:Sixty-four primary breast cancer patients on follow-up (a median of 8.3 years post surgery) who were disease free had sequential bone marrow aspirates and blood samples taken for the measurement of disseminated tumour cells (DTCs), circulating tumour cells (CTCs) by CellSearch and qPCR measurement of overlapping (96-bp and 291-bp) amplicons in circulating free DNA (cfDNA).Results:The presence of CTCs was correlated with the presence of DTCs measured by immunocytochemistry (P=0.01) but both were infrequently detected. Increasing cfDNA concentration correlated with ER, HER2 and triple-negative tumours and high tumour grade, and the 291-bp amplicon was inversely correlated with DTCs measured by CK19 qRT-PCR (P=0.047).Conclusion:Our results show that breast cancer patients have evidence of MRD for many years after diagnosis despite there being no overt evidence of disease. The inverse relationship between bone marrow CK19 mRNA and the 291-bp amplicon in cfDNA suggests that an inverse relationship between a measure of cell viability in the bone marrow (DTCs) and cell death in the plasma occurs during the dormancy phase of breast cancer.
Filipovic A, Gronau JH, Green AR, et al., 2011, Biological and clinical implications of nicastrin expression in invasive breast cancer, Breast Cancer Res Treat, Vol: 125, Pages: 43-53, ISSN: 1573-7217
Nicastrin is an essential component of the gamma secretase (GS) enzyme complex, required for its synthesis and recognition of substrates for proteolytic cleavage. The purpose of this study was to investigate whether nicastrin has prognostic value or potential as a therapeutic target in breast cancer (BC). The suitability of nicastrin as a target in BC was assessed using BC tissue microarrays (TMAs) (n = 1050), and its biological role in vitro was evaluated in BC cell lines following gene silencing. Nicastrin blocking antibodies were developed and evaluated for their suitability as potential clinical therapeutics. TMA and cell line analysis confirmed that nicastrin expression was upregulated in BC compared to normal breast cells. In TMA patient samples, high nicastrin expression was observed in 47.5% of cases and correlated with ERalpha expression, patient age, and tumor grade. In pre-defined subset analysis, high nicastrin expression predicted for worse BC specific survival in the ERalpha -ve cohort. In vitro gene silencing of nicastrin resulted in disruption of the GS complex and a decrease in notch1 cleavage. This was sufficient to increase E-cadherin expression and its co-localization with p120 catenin at cell-cell junctions in MCF7 cells. Nicastrin silencing in invasive MDA-MB-231 cells resulted in loss of vimentin expression and a marked reduction in both cell motility and invasion; which was concomitant with the de novo formation of cell-cell junctions characterized by the colocalization of p120 catenin and F-actin. These data indicate that nicastrin can function to maintain epithelial to mesenchymal transition during BC progression. Anti-nicastrin polyclonal and monoclonal antibodies were able to decrease notch1 and vimentin expression and reduced the invasive capacity of BC cells in vitro. This supports our hypothesis that a nicastrin blocking antibody could be used to limit metastatic dissemination in invasive BC.
Filipovic A, Green A, Shao D, et al., 2010, Nicastrin Reveals Gamma-Secretase Independent Function in Breast Cancer Cells and Can Be Targeted by a Blocking Monoclonal Antibody To Reduce Breast Cancer Cell Proliferation and Invasion, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Yague E, Raguz S, 2010, Escape from stress granule sequestration: another way to drug resistance?, Biochemical Society Transactions, Vol: 38, Pages: 1537-1542, ISSN: 0300-5127
Overexpression of P-glycoprotein, encoded by the MDR1 (multidrug resistance 1) gene, is often responsible for multidrug resistance and chemotherapy failure in cancer. We have demonstrated that, in leukaemic cells, P-glycoprotein expression is regulated at the translational level. More recently, we have shown that in cells overexpressing P-glycoprotein, MDR1 mRNA does not aggregate into translationally silent stress granules. Importantly, this is not unique for MDR1, since other transcripts encoding transmembrane proteins, and which are thus translated at the endoplasmic reticulum, follow the same pattern. By using a series of chimaeric transcripts, we have demonstrated that transcript localization at the endoplasmic reticulum bypasses the signals dictating stress granule sequestration. Polysome profile analyses and protein synthesis experiments indicate that, upon stress withdrawal, endoplasmic-reticulum-bound transcripts resume translation faster than those at the cytosol, which have been sequestered into stress granules. This may represent a novel mechanism by which drug-resistant cells respond quickly to stress, helping them to survive the cytotoxic effect of chemotherapeutic drugs.
Unsworth H, Raguz S, Edwards HJ, et al., 2010, mRNA escape from stress granule sequestration is dictated by localization to the endoplasmic reticulum, FASEB Journal, Vol: 24, Pages: 3370-3380, ISSN: 0892-6638
In mammalian cells, cytotoxic stress triggers several signaling cascades that converge in the phosphorylation of translation initiation factor 2α, shuttling of nuclear RNA-binding proteins such as TIA-1 to the cytoplasm, and aggregation of most cellular mRNAs into TIA-1-containing stress granules (SGs). As a result, protein synthesis is greatly impaired. Here we describe different dynamics of endogenous transcripts according to their cellular location, in response to stress. While cytosolic mRNAs aggregate into SGs, endoplasmic reticulum (ER) -bound transcripts escape sequestration. This has been specifically demonstrated using the multidrug resistance transporter gene (MDR1) as a model and showing that chimeric RNA constructs can be directed to the cytosol or tethered to the ER depending on the nature of the chimera, in response to stress. In addition, polysome profile analyses indicate that, on stress, ribosomes do not disengage from ER-associated transcripts (puromycin insensitive) and recover their translation status faster than SG-targeted cytosolic mRNAs once the stress is lifted. These findings have important implications for cell survival given that many membrane proteins, which are translated at the ER, have important roles in detoxification
Yague E, 2010, Multidrug resistance, Methods of Cancer Diagnosis, Therapy, and Prognosis, Editors: Hayat, Publisher: Springer Verlag, Pages: 121-133, ISBN: 9789048131853
Yague E, Raguz S, 2010, Multidrug resistance, Methods of Cancer Diagnosis, Therapy, and Prognosis, Editors: Hayat, Publisher: Springer Verlag, Pages: 121-133, ISBN: 9789048131853
Balasubramanian R, Rashied S, Filipovic A, et al., 2009, Gammasecretase Inhibition Results in Both Caspase Dependant and Independent Apoptosis in Breast Cancer Cell Lines, 32nd Annual San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 689S-689S, ISSN: 0008-5472
Rasul S, Balasubramanian R, Filipovic A, et al., 2009, Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells, British Journal of Cancer, Vol: 100, Pages: 1879-1888, ISSN: 0007-0920
γ-Secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their intracellular domains to the nucleus. Notch overexpression has been associated with breast, colon, cervical and prostate cancers. We tested the effect of three different γ-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 μM and above but had a minimal effect on the non-malignant breast lines. GSI1 was also cytotoxic for a wide variety of cancer cell lines in the NCI60 cell screen. GSI1 treatment resulted in a marked decrease in γ-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the γ-secretase components or ligands. Flow cytometric and western blot analyses indicated that GSI1 induces a G2/M arrest leading to apoptosis, through downregulation of Bcl-2, Bax and Bcl-XL. GSI1 also inhibited proteasome activity. Thus, the γ-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent a novel therapy in breast cancer.
Filipovic A, Rashied S, Balasubramanian R, et al., 2009, Inhibiting nicastrin (NCT) stabilizes expression of e-cadherin and has potential in inducing mesenchymal to epithelial transition in breast cancer (BC)., 31st Annual San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 224S-224S, ISSN: 0008-5472
Payne RE, Yaguee E, Slade MJ, et al., 2009, Measurements of EGFR expression on circulating tumor cells are reproducible over time in metastatic breast cancer patients, PHARMACOGENOMICS, Vol: 10, Pages: 51-57, ISSN: 1462-2416
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- Citations: 53
Raguz S, Yaguee E, 2008, Resistance to chemotherapy: new treatments and novel insights into an old problem, British Journal of Cancer, Vol: 99, Pages: 387-391, ISSN: 0007-0920
Resistance to cancer chemotherapeutic treatment is a common phenomenon, especially in progressive disease. The generation of cellular models of drug resistance has been pivotal in unravelling the main effectors of resistance to traditional chemotherapy at the molecular level (i.e. intracellular drug inactivation, detoxifying systems, defects in DNA repair, apoptosis evasion, membrane transporters and cell adhesion). The development of targeted therapies has also been followed by resistance, reminiscent of an evolutionary arms race, as exemplified by imatinib and other BCR-ABL inhibitors for the treatment of chronic myelogenous leukaemia. Although traditionally associated with the last stages of the disease, recent findings with minimally transformed pretumorigenic primary human cells indicate that the ability to generate drug resistance arises early during the tumorigenic process, before the full transformation. Novel technologies, such as genome profiling, have in certain cases predicted the outcome of chemotherapy and undoubtedly have tremendous potential for the future. In addition, the novel cancer stem cell paradigm raises the prospect of cell-targeted therapies instead of treatment directed against the whole tumour.
Raguz S, Randle RA, Sharpe ER, et al., 2008, Production of P-glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first-line chemotherapy in advanced breast cancer, INTERNATIONAL JOURNAL OF CANCER, Vol: 122, Pages: 1058-1067, ISSN: 0020-7136
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- Citations: 15
Randle RA, Raguz S, Higgins CF, et al., 2007, Role of the highly structured 5′-end region of <i>MDR1</i> mRNA in P-glycoprotein expression, BIOCHEMICAL JOURNAL, Vol: 406, Pages: 445-455, ISSN: 0264-6021
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- Citations: 21
Yague E, Arance A, Kubitza L, et al., 2007, Ability to acquire drug resistance arises early during the tumorigenesis process, CANCER RESEARCH, Vol: 67, Pages: 1130-1137, ISSN: 0008-5472
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- Citations: 53
Raguz S, De Bella MT, Slade MJ, et al., 2005, Expression of <i>RPIP9</i> (<i>Rap2 interacting protein 9</i>) is activated in breast carcinoma and correlates with a poor prognosis, INTERNATIONAL JOURNAL OF CANCER, Vol: 117, Pages: 934-941, ISSN: 0020-7136
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- Citations: 15
Yague E, Raguz S, 2005, Drug resistance in cancer, British Journal of Cancer, Vol: 93, Pages: 973-976, ISSN: 0007-0920
Cancer Research UK has recently sponsored a meeting, organized by the UK Medical Research Council, on cancer drug resistance. Several of the molecular mechanisms responsible for this clinical outcome, such as DNA interstrand crosslink repair, apoptosis evasion, cytochrome P450 and P-glycoprotein, were discussed. There was a special focus on leukaemia, breast and ovarian cancer, and the potential use of positron-emission tomography to study anticancer-drug resistance. The progress made in translating these findings to the clinic, like Gefitinib, P-glycoprotein phenotyping, or genome-wide analysis technology, was also discussed.
Yagüe E, Higgins CF, Raguz S, 2004, Complete reversal of multidrug resistance by stable expression of small interfering RNAs targeting MDR1, GENE THERAPY, Vol: 11, Pages: 1170-1174, ISSN: 0969-7128
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- Citations: 94
Raguz S, De Bella MT, Tripuraneni G, et al., 2004, Activation of the <i>MDR1</i> upstream promoter in breast carcinoma as a surrogate for metastatic invasion, CLINICAL CANCER RESEARCH, Vol: 10, Pages: 2776-2783, ISSN: 1078-0432
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- Citations: 37
Antoniou M, Harland L, Mustoe T, et al., 2003, Transgenes encompassing dual-promoter CpG islands from the human TBP and HNRPA2B1 loci are resistant to heterochromatin-mediated silencing., Genomics, Vol: 82, Pages: 269-279, ISSN: 0888-7543
The genetic elements that are responsible for establishing a transcriptionally competent, open chromatin structure at a region of the genome that consists only of ubiquitously expressed, housekeeping genes are currently unknown. We demonstrate for the first time through functional analysis in stably transfected tissue culture cells that transgenes containing methylation-free CpG islands spanning the dual divergently transcribed promoters from the human TATA binding protein (TBP)-proteasome component-B1 (PSMB1) and heterogeneous nuclear ribonucleoprotein A2/B1 (HNRPA2B1)-heterochromatin protein 1Hs-gamma (chromobox homolog 3, CBX3) gene loci are sufficient to prevent transcriptional silencing and a variegated expression pattern when integrated within centromeric heterochromatin. In addition, only transgene constructs extending over both the HNRPA2B1 and the CBX3 promoters, and not the HNRPA2B1 promoter alone, were able to confer high and stable long-term EGFP reporter gene expression. These observations suggest that methylation-free CpG islands associated with dual, divergently transcribed promoters possess an independent dominant chromatin opening function and may therefore be major determinants in establishing and maintaining a region of open chromatin at housekeeping gene loci.
Yagüe E, Armesilla AL, Harrison G, et al., 2003, P-glycoprotein (<i>MDR1</i>) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 278, Pages: 10344-10352, ISSN: 0021-9258
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- Citations: 108
Raguz S, Hobbs C, Yagüe E, et al., 1998, Muscle-specific locus control region activity associated with the human desmin gene., Dev Biol, Vol: 201, Pages: 26-42, ISSN: 0012-1606
We describe the reproduction of the full pattern of expression of the muscle-specific desmin gene in transgenic mice using a 240-kb genomic clone spanning the human desmin locus. Analysis of RNA from adult tissues demonstrated that this fragment possesses all the necessary genetic regulatory elements required to provide reproducible, site-of-integration-independent, physiological levels of tissue-specific expression that is directly proportional to transgene copy number in all muscle cell types. In situ hybridization revealed that in marked contrast to murine desmin which is strongly expressed in the myotome of the somites, skeletal muscles, the heart, and smooth muscle of the vasculature by 9.5 days postcoitum, human desmin transgene expression was completely absent from smooth muscles, was very weak and restricted to the atrium and outflow tract within the heart, and was expressed at only 5% of murine desmin mRNA levels within the myotome of the somites. The spatial distribution and levels of human and mouse desmin expression were not coincident until 14.5 days postcoitum. Immunohistochemical analysis of human embryos at comparable stages of development showed that this transgene faithfully reproduces the human and not the mouse developmental expression pattern for this gene in transgenic mice. These results indicate that the 240-kb desmin genomic clone is capable of establishing an independent, chromatin domain in transgenic mice and provides the first definitive data for muscle-specific locus control region activity. In addition, our results demonstrate that the behavior of human transgenes in mice should, whenever possible, be compared to expression patterns for that gene in human embryonic as well as adult tissues.
Yage E, Mehak-Zunic M, Morgan L, et al., 1997, Expression of CEL2 and CEL4, two proteins from Agaricus bisporus with similarity to fungal cellobiohydrolase I and beta-mannanase, respectively, is regulated by the carbon source., Microbiology (Reading), Vol: 143 ( Pt 1), Pages: 239-244, ISSN: 1350-0872
Two new cellulose-growth specific (cel) cDNAs, cel2 and cel4, have been isolated from an Agaricus bisporus cDNA expression library by immunoscreening with an A. bisporus anti-'endoglucanase' antibody. The deduced amino acid sequences showed that both CEL2 and CEL4 proteins have a modular structure consisting of a fungal-type cellulose-binding domain (CBD) and a catalytic domain separated by a linker region rich in Pro, Ser and Thr. The CEL2 and CEL4 catalytic domains were homologous to fungal cellobiohydrolases (CBH) in family 7 and to fungal mannanases in family 5 of the glycosyl hydrolases, respectively. A previously isolated cDNA derived from a constitutive gene was also sequenced. The deduced amino acid sequence corresponded to 5-aminolaevulinic acid synthase (ALA), the first enzyme in the haem biosynthetic pathway, and was most similar to other fungal ALAs. RNA analysis showed that the expression of cel2 and cel4 genes was induced by cellulose and repressed by glucose, fructose and lactose. The soluble cellulose derivative CM-cellulose induced mRNA accumulation for cel1 but not cel2, cel3 or cel4. Mannitol, maltose, sorbitol and glycerol decreased cel2 and cel4 mRNA levels to different extents. cel1, cel2, cel3 and cel4 mRNAs all disappeared after the addition of glucose with apparent half-lives of less than 20 min. Whether cel mRNAs have short half-lives or glucose affects the stability of cel transcripts remains to be investigated.
Yagüe E, Chow CM, Challen MP, et al., 1996, Correlation of exons with functional domains and folding regions in a cellulase from Agaricus bisporus., Curr Genet, Vol: 30, Pages: 56-61, ISSN: 0172-8083
The cellulase gene cel3 has been isolated from Agaricus bisporus and sequenced. The 5'-end of the cel3 transcript was determined by primer extension and S1 nuclease protection. Putative regulatory elements have been identified in the cel3 promoter and 3'-untranslated regions. The cel3 coding region is interrupted by six short introns, two of which separate the coding regions for the three modules in the CEL3 protein: cellulose-binding domain, linker region, and catalytic domain. Three of the remaining four introns are positioned in regions coding for loops between structural moieties. Intron positions are conserved between cel3 and other related cellulases.
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