Abstract
We developed an in situ tumor vaccine with the ability to elicit antitumor immunity. This vaccine comprised an E1B-deleted oncolytic adenovirus expressing beta-defensin-2 (Ad-BD2-E1A) for releasing tumor antigens, recruiting and activating plasmacytoid dendritic cells (pDCs). Intratumoral injections...
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PMID: 19532135
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Abstract
A modified in vitro ligation approach was developed to construct a double-targeted, E1B55k-deleted CRAd. The method allowed the incorporation of a tumor-specific promoter, e.g. the heat-shock protein 70 (hsp70) promoter, upstream of E1a, deletion of the E1B55k gene, and HR-free cloning of the recomb...
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PMID: 19200390
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Abstract
The ligase IV/XRCC4 complex plays a central role in DNA double-strand break repair by non-homologous end joining (NHEJ). During adenovirus infection, NHEJ is inhibited by viral proteins E4 34k and E1B 55k, which redirect the Cul5/Rbx1/Elongin BC ubiquitin E3 ligase to polyubiquitinate and promote de...
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PMID: 18952251
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Changqing Su,
Hui Cao,
Shuping Tan,
Yao Huang,
Xiaoyuan Jia,
Lixin Jiang,
Kai Wang,
Ying Chen,
Ju Long,
Xinyuan Liu,
Mengchao Wu,
Xiaobing Wu and
Qijun Qian
Abstract
We generated a triple-regulated p53-armed CRAd, SG600-p53, in which the partially deleted E1a and E1b genes are regulated under the human telomerase reverse transcriptase promoter and the hypoxia response element. SG600-p53 was proven to be effective both in vitro and in vivo. In this study, the pre...
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PMID: 18703561
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Abstract
We examined properties of p53 in normal human cells infected by E1B mutant viruses that display defective entry into the late phase or viral late mRNA export. The steady-state concentrations of p53 were significantly higher in cells infected by the E1B 55 kDa null mutant Hr6 or three mutants carryin...
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PMID: 18632130
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Abstract
We show that the degradation of individual targets can occur independently of other substrates. Furthermore, we identify separation-of-function mutant forms of E1b55K that can distinguish substrates for binding and degradation. Our results identify distinct regions of E1b55K that are involved in sub...
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PMID: 18614635
PDF is available here.
Abstract
We show that SCCA2 promoter was active in SCCA2-producing human cervical cancer cell lines, including Cx, Cxwj, SiHa and HeLa cells, but relatively quiescent in normal cervical epithelial cells. We then developed a conditionally replicating adenovirus, designated Ad-KFH, under the transcriptional co...
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PMID: 18497852
PDF is available here.
Abstract
We examined whether E1B-AP5 function was integral to these pathways. Here, we show a novel role for E1B-AP5 as a key regulator of ATR signaling pathways activated during Ad infection. E1B-AP5 is recruited to viral replication centers during infection, where it colocalizes with ATR-interacting protei...
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PMID: 18480432
PDF is available here.
Abstract
We have examined the influence of Ad5 E1A and E1B gene products on mouse lung carcinogenesis and inflammation by generation and characterization of lung-specific transgenic mouse models. Here, we show that either the Ad5 E1A 243-amino-acid (aa) protein or the E1B 58-kDa protein was dominantly expres...
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PMID: 18524829
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Abstract
We show here that the relevant activity on chromosome 21 maps to RUNX1. RUNX1 proteins are transcription factors that serve as scaffolds for the assembly of proteins that regulate transcription and RNA processing. After transfection, the RUNX1a, RUNX1b, and RUNX1-DeltaN variants allowed E4orf6-direc...
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PMID: 18417565
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Abstract
We performed a comprehensive mutational analysis to assign further transforming functions of Ad5 E1B-55K to distinct domains within the viral polypeptide. Results from these studies show that the functions required for transformation are encoded within several patches of the 55K primary sequence, in...
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PMID: 18212738
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Abstract
We have shown previously that expression of several cell cycle-regulating genes is markedly affected by the Ad E1b gene in WI-38 human lung fibroblast cells (X. Rao, et al., Virology 350:418-428, 2006). In the current study, we show that the Ad E1B55K region is required to enhance cyclin E expressio...
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PMID: 18234796
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Abstract
We unravel a novel activity of E1B-55K by demonstrating that it drastically stimulates the post-translational modification of p53 by the ubiquitin-like SUMO modifier. Consistent with this finding the extent of p53 SUMOylation is highly elevated in adenovirus transformed cell lines. E1B-55K-mediated...
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PMID: 18461721
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Abstract
We reasoned that combined treatment of cancer cells with ZD55-MnSOD and 5-FU might have a synergistic effect. In vitro experiments with SW620 colorectal carcinoma cell line demonstrated that it was sensitive to ZD55-MnSOD, especially most sensitive to ZD55-MnSOD plus 5-FU treatment. Treatment with b...
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PMID: 17632733
PDF is available here.
Abstract
These results suggest that AxdAdB-3 could be a promising tool for virotherapy against prostate cancer in patients with disease resistant to hormonal therapy....
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PMID: 18158069
PDF is available here.
Abstract
We explored the connection between AAV helper functions supplied by adenovirus and cellular DNA repair proteins. The adenoviral E1b55K/E4orf6 proteins induce degradation of the cellular Mre11 repair complex (MRN) to promote productive adenovirus infection. These viral proteins also augment recombina...
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PMID: 17898048
PDF is available here.
Abstract
We discovered that in selective cell types, it potently activates the transcriptional activity of the tumor suppressor p53. This action, however, is not dependent on the downstream of either the Wnt or the planar polarity pathways. Dishevelled signals to the first 50 amino acids of p53, which is the...
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PMID: 17593335
PDF is available here.
Abstract
We have previously shown that E1B 19kDa and E1B 55kDa gene-deleted Ad (Ad-DeltaE1B19/55) exhibits improved tumor-specific replication and cell lysis, leading to an enhanced antitumor effect. In an effort to increase cancer cell selectivity of a replicating adenovirus, we first generated 11 E1A mutan...
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PMID: 17725410
PDF is available here.
Abstract
We report that the adenoviral oncoprotein E1B55K directly binds to endogenous SSBP2 protein and sequesters it into juxtanuclear bodies in adenovirally transformed human embryonic kidney (HEK) 293 cells. Similarly, transient expression of E1B55K in IMR90 fibroblasts and HeLa cells result in the forma...
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PMID: 17311003
PDF is available here.
Abstract
These results demonstrate that expression of anti-apoptosis genes can enhance culture performance and increase MAb titers for mammalian CHO cell cultures especially under conditions such as extended fed-batch bioreactor operation.
(c) 2006 Wiley Periodicals, Inc....
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PMID: 17099908
PDF is available here.
Abstract
Adenovirus type 40 and 41 (Ad40, Ad41), which belong to human adenovirus subgroup F, are called fastidious adenoviruses due to their property of poor growth in cultured cell lines in vitro The effect of expression of exogenous E1B55K in Hep2 on Ad41 replication in this cell line was investigated. E1...
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PMID: 17894226
PDF is available here.
Abstract
We show here that DNA ligase IV, which performs the joining step of NHEJ, is degraded as a consequence of adenovirus infection. Degradation is dependent upon E4 34k and E1b 55k, functional proteasomes, and the activity of cellular cullin 5, a component of the adenoviral ubiquitin ligase. DNA ligase...
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PMID: 17459921
PDF is available here.
Abstract
The RGD-fiber modification strategy enhanced the infectivity, replication, and oncolytic effects of the E1A, E1B double-restricted oncolytic adenovirus for CAR-deficient biliary cancers. In addition, it preserved the merit of excellent safety of the double-restricted virus for normal cells. These re...
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PMID: 17505007
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Abstract
A replication-competent adenoviral vector deficient for expression of the early E1B55K protein has been applied in clinical studies. The vector, however, was not fully effective for the treatment of human cancer. In this study, the E1A gene (which encodes an Rb-binding domain protein) of the adenovi...
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PMID: 17518613
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Abstract
We have investigated the requirements for CRM1-mediated nuclear export and SUMO1 conjugation of the adenovirus E1B-55K protein during productive infection. Our data show that CRM1 is the major export receptor for E1B-55K in infected cells. Functional inactivation of the E1B-55K CRM1-dependent nuclea...
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PMID: 17428914
PDF is available here.
Abstract
The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating...
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PMID: 17409411
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Abstract
We expressed E1B in several tumor cell lines that express wild type p53. Here we show that E1B strongly suppresses the expression of p53 target genes such as p21 and Puma-alpha in normal growth conditions or after cells were treated with p53-activating chemotherapeutic agents, suggesting that E1B-me...
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PMID: 17209038
PDF is available here.
Abstract
Ad37 induces an acute immunopathologic response in the C57BL/6J mouse cornea, despite an absence of viral replication. This new animal model of Ad37 keratitis will facilitate studies of the molecular pathogenesis of the disorder....
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PMID: 17251478
PDF is available here.
Abstract
These results suggest that E1Blarge interacts with NF-kappaB to prevent transcription and down regulate proinflammatory cytokine IL-8 production....
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PMID: 17565687
PDF is available here.
Abstract
We designed and expressed a dominant-negative mutant form of cullin 5 in HeLa cells before infection with wild-type Ad5 or the E1B-55K null mutant dl1520. The dominant-negative cullin 5 protein stabilized p53 and the MRN complex, indicating that it inhibited the viral ubiquitin-protein ligase but ha...
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PMID: 17079297
PDF is available here.
Abstract
We performed genetic and biochemical analyses to assess the attributes of the remaining E1B proteins (E1B-156R, E1B-93R, and E1B-84R). Our results show that E1B-156R, which comprises the 79 amino-terminal and 77 carboxy-terminal amino acids of E1B-55K, also enhances focal transformation of primary r...
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PMID: 17050591
PDF is available here.
Qi Q Zhang,
Guihua G Chen,
Linhui L Peng,
Xinghua X Wang,
Yang Y Yang,
Chen C Liu,
Wenfang W Shi,
Changqing C Su,
Hongping H Wu,
Xinyuan X Liu,
Mengchao M Wu and
Qijun Q Qian
Abstract
CNHK500 greatly reduced side effects in normal cells via dual control of adenoviral essential genes while still preserving potent antitumor efficacy on broad-spectrum cancer cells in vitro and in vivo. It can be used as a powerful therapeutic agent not only for liver cancers but also for other solid...
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PMID: 17085667
PDF is available here.
Abstract
We identified a total of 345 genes with expression changes of two-fold or greater affected by wild-type adenovirus compared with its E1b-deleted counterpart. The gene array data were confirmed by quantitative real-time PCR and Western blot. E1B proteins affect the expression of a diverse range of ge...
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PMID: 16542696
PDF is available here.
Abstract
Clinical efficacy of adenovirus-mediated cancer gene therapy has been limited thus far. To improve its oncolytic effect, a replication-competent adenoviral vector was previously constructed to express high levels of p53 at a late time point in the viral life cycle. p53 expression from this vector im...
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PMID: 16470212
PDF is available here.
Abstract
The strategy that transcribes short hairpin RNAs (shRNAs) by RNA polymerase II promoters is expected to present flexible approaches for regulating the patterns of shRNA expression. The capacity of generating shRNA by a modified adenovirus RNA polymerase II E1b promoter was studied. This 49bp promote...
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PMID: 16386806
PDF is available here.
Abstract
We discuss the mechanisms underlying these approaches and their perspectives for cancer therapy....
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PMID: 16690321
PDF is available here.
Abstract
We have recently constructed a conditionally replicating Ad5 AdDeltaEP-TETP inducing tumour regression in a xenograft mouse model. For further improvement of this vector, we introduced four genetic modifications and analysed the viral cytotoxicity in a large panel of melanoma cell lines and patient-...
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PMID: 16482201
PDF is available here.
Abstract
We now show that co-infection of recombinant adenoviruses expressing E1A/E1B and hCDC5 promotes cell cycle re-entry and G2/M progression in post-mitotic cardiomyocytes. Co-expression of E1A/E1B and hCDC5 induced nuclear localization of cyclin-dependent kinase 1 and cyclin B1, and was sufficient to p...
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PMID: 16482203
PDF is available here.
Abstract
Our results showed that the production of hydrogen peroxide derived from MnSOD dismutation activated caspase-8, which might down-regulate Bcl-2 expression and induce Bax translocation to mitochondria. Subsequently, Bax translocation enhanced the release of apoptosis-initiating factor and cytochrome...
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PMID: 16618754
PDF is available here.
Abstract
We have shown that oncolytic adenovirus Ad-DeltaE1B19/55, deleted for sequence encoding E1B 19-kDa and E1B 55-kDa proteins, exhibits marked enhancement in cytolytic and apoptotic activity [Kim, J., Cho, J.Y., Kim, J.H., Jung, K.C., and Yun, C.O. (2002). Cancer Gene Ther. 9, 725-736]. In the current...
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PMID: 16610926
PDF is available here.
Abstract
TD55-TRAIL has better security than ZD55-TRAIL in normal cells. So, the security of medication will be improved with dual targeting vector TD55. TD55-harbored gene as TD55-TRAIL has stronger effect than TD55 in inducing apoptosis of tumor cells....
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PMID: 16613667
PDF is available here.
Abstract
We have previously reported that nuclear accumulation of the human transcription factor YB-1 by regulating the adenoviral E2 late promoter facilitates viral DNA replication of E1-deleted adenovirus vectors which are widely used for cancer gene therapy. Here we report the promotion of virus-mediated...
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PMID: 16571807
PDF is available here.
Abstract
We have explored further the effect of p53 on adenoviral replicative lysis. Using well-characterized cells expressing a functional p53 (A549, K1neo, RKO) and isogenic derivatives that do not (K1scx, RKOp53.13), we show that virus replication, late virus protein expression and both wtAd5 and ONYX-015...
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PMID: 16247442
PDF is available here.
Abstract
These results suggest that antigen-specific T cell repertoire is substantially affected by the antigen dose employed in vivo as well as in vitro....
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PMID: 16431877
PDF is available here.
John A JA Howe,
Peter P Pelka,
Doug D Antelman,
Chris C Wilson,
Doug D Cornell,
Wendy W Hancock,
Murali M Ramachandra,
Jenny J Avanzini,
Mark M Horn,
Ken K Wills,
Suganto S Sutjipto and
Robert R Ralston
Abstract
We tested complementation of rAd vectors using sequential transfection of individual E1A and E1B expression cassettes into A549 human lung tumor cells, which support highly efficient replication of wild type adenovirus. We found that E1A function could be complemented in A549 cells by the mutant E1A...
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PMID: 16246392
PDF is available here.
Abstract
We have used a genetic strategy to identify different viral genes that influence adenovirus type 5 (Ad5) spread in an epithelial cancer cell line. An Ad5 mutant (dl327; lacking most of the E3 region) with the restricted-spread (small-plaque) phenotype was randomly mutagenized with UV, and 27 large-p...
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PMID: 16439556
PDF is available here.
Abstract
We have therefore examined the phenotypes exhibited by viruses carrying mutations in the E1B 55-kDa protein coding sequence in normal human fibroblast (HFFs). Ad5 replicated significantly more slowly in HFFs than it does in tumor cells, a difference that is the result of delayed entry into the late...
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PMID: 16378998
PDF is available here.
Abstract
Adenovirus continues to be an important model system for investigating basic aspects of cell biology. Interactions of several cellular proteins with E1A conserved regions (CR) 1 and 2, and inhibition of apoptosis by E1B proteins are required for oncogenic transformation. CR2 binds RB family members,...
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PMID: 16299528
PDF is available here.
Abstract
We discuss the abundance and likely core location of LH3 in the virion and the possible derivation of the E1B 55-kDa gene from the LH3 gene....
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PMID: 16112161
PDF is available here.
Abstract
We use an expanded panel of attenuated adenoviruses to study adenovirus-mediated cytotoxicity of MCL cells. Our results demonstrate: 1) adenovirus infection of MCL cells despite the absence of receptor/coreceptor molecules known to be important for adenovirus infection of other cells types; 2) cytot...
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PMID: 16263418
PDF is available here.
Abstract
We prepared E1B55K-deleted adenovirus and investigated its cytopathic effects in primary lung cancer cells to evaluate the possibility of its application in gene therapy. A p53 wild-type small cell lung cancer cell line (SBC3) and three p53 mutant cell lines (SBC5, small cell lung cancer; PC3, adeno...
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PMID: 16211279
PDF is available here.
Abstract
We show that during early phase of Ad infection, a fraction of p53 is targeted to the mitochondria. In virus infected cells, a large fraction of the viral antiapoptosis protein E1B-19K is also localized in mitochondria during early and late phases of infection. Coimmunoprecipitation analysis has rev...
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PMID: 16007153
PDF is available here.
Abstract
We are currently conducting clinical trials of E1A gene therapy for patients with ovarian cancer. The adenovirus type 5 E1A gene suppresses growth of ovarian cancer cells that overexpress HER-2/neu (HER2) and growth of some--but not all--that express low HER2. In HER2-overexpressing cells, suppressi...
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PMID: 16166319
PDF is available here.
Abstract
We hypothesized that the functional redundancy between viral gene products might limit selectivity and/or potency with this approach. Antiviral immune inducers of apoptosis (eg TNF-alpha) have not been thoroughly investigated in previous studies. We therefore explored whether deletion of functionall...
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PMID: 15920462
PDF is available here.
Abstract
We have analysed the expression of several immunomodulatory molecules on the surface of a set of human cell lines transformed with either Ad12 or Ad5. Human cells transformed with Ad12 demonstrated reduced expression of cell surface LFA-3, Fas and MHC class I when compared to Ad5-transformed cells....
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PMID: 15963548
PDF is available here.
Abstract
We show that resistant tumor cell lines fail to provide the RNA export functions of E1B-55K necessary for ONYX-015 replication; viral 100K mRNA export is necessary for host protein shutoff. However, heat shock rescues late viral RNA export and renders refractory tumor cells permissive to ONYX-015. T...
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PMID: 16023599
PDF is available here.
Abstract
We show that E4orf6 interacts with pp32/leucine-rich acidic nuclear protein (LANP). E4orf6 exports pp32/LANP from the nucleus to the cytoplasm with its binding partner, HuR, which binds to an AU-rich element (ARE) present within many protooncogene and cytokine mRNAs. We found that ARE-mRNAs, such as...
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PMID: 15983058
PDF is available here.