Abstract:
:Deregulation of translation initiation factors contributes to many pathogenic conditions, including cancer. Here, we report the definition of a novel regulatory pathway for translational initiation with possible therapeutic import in cancer. Specifically, we found that casein kinase 1ε (CK1ε) is highly expressed in breast tumors and plays a critical role in cancer cell proliferation by controlling mRNA translation. Eukaryotic translation initiation factor eIF4E, an essential component of the translation initiation complex eIF4F, is downregulated by binding the negative-acting factor 4E-BP1. We found that genetic or pharmacologic inhibition of CK1ε attenuated 4E-BP1 phosphorylation, thereby increasing 4E-BP1 binding to eIF4E and inhibiting mRNA translation. Mechanistic investigations showed that CK1ε interacted with and phosphorylated 4E-BP1 at two novel sites T41 and T50, which were essential for 4E-BP1 inactivation along with increased mRNA translation and cell proliferation. In summary, our work identified CK1ε as a pivotal regulator of mRNA translation and cell proliferation that acts by inhibiting 4E-BP1 function. As CK1ε is highly expressed in breast tumors, these findings offer an initial rationale to explore CK1ε blockade as a therapeutic strategy to treat cancers driven by deregulated mRNA translation.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Shin S,Wolgamott L,Roux PP,Yoon SOdoi
10.1158/0008-5472.CAN-13-1175subject
Has Abstractpub_date
2014-01-01 00:00:00pages
201-11issue
1eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-13-1175journal_volume
74pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::The role of natural killer group 2, member D receptor (NKG2D)-expressing natural killer (NK) cells in tumor immunosurveillance is now well established. Nevertheless, tumor progression occurs despite tumor immunosurveillance, leading to cancer persistence in immunocompetent hosts. STAT3 plays a pivotal role both in onc...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-4540
更新日期:2011-03-01 00:00:00
abstract::C19ORF5 is a sequence homologue of microtubule-associated proteins MAP1A/MAP1B of unknown function, except for its association with mitochondria-associated proteins and the paclitaxel-like microtubule stabilizer and candidate tumor suppressor RASSF1A. Here, we show that when overexpressed in mammalian cells the recomb...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-3865
更新日期:2005-05-15 00:00:00
abstract::Mutations of the p53 gene constitute one of the most frequent genetic alterations in squamous cell carcinoma of the head and neck (SCCHN). In this study, we introduced wild-type p53 into two separate SCCHN cell lines via a recombinant adenoviral vector, Ad5CMV-p53. Northern blotting showed that following infection by ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-07-15 00:00:00
abstract::Several properties of four 1-deaza-7,8-dihydropteridines were compared with those of each other and with those of colchicine, nocodazole, podophyllotoxin, and vincristine. Compound NSC 370147 was more active than the other compounds of this type with respect to inhibition of proliferation of cultured L1210 cells and t...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-03-15 00:00:00
abstract::The growth inhibitory effects of combinations of antifolates on hepatoma cells in culture have been examined. In these studies methotrexate or the lipophilic inhibitors of dihydrofolate reductase were used with the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolate (PDDF). Under certain conditions partial ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-10-15 00:00:00
abstract::Formalin-fixed, paraffin-embedded tissues from 108 cases of invasive carcinoma of the uterine cervix, consisting of 40 cases of adenocarcinoma, 44 cases of adenosquamous carcinoma, and, as a control, 24 cases of squamous cell carcinoma were examined for the presence of human papillomavirus (HPV) DNA by in situ hybridi...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-02-15 00:00:00
abstract::The requirement for cell division in the malignant transformation of A31-714 cells, a subclone derived from BALB/3T3, by 3-methylcholanthrene was investigated using the property of the high susceptibility of this clone to density-dependent inhibition of cell growth. Treatment with 3-methylcholanthrene did not induce t...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1975-07-01 00:00:00
abstract::Bloom syndrome is an autosomal recessive disorder whose characteristics include an increased risk for many types of cancers. In contrast to the homozygous mutations of Bloom syndrome, heterozygous carriers of BLM mutations may be at increased risk for developing colorectal cancer. We have screened 2,333 Jewish individ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-04-15 00:00:00
abstract::Low-density lipoprotein (LDL) could be used as a carrier of chemotherapeutic agents to neoplastic cells that overexpress LDL receptors (rLDL), but LDL is difficult to obtain and handle. Recently, it was observed that a protein-free emulsion resembling the lipid portion of LDL (LDE) behave like native LDL when injected...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-09-01 00:00:00
abstract::Microdialysis is a technique that enables measurement of extracellular concentrations of unbound analytes. A small probe with a semipermeable membrane is implanted in tissue and constantly perfused. Small analytes in the interstitial fluid diffuse into the perfusate and are collected. Often, microdialysate concentrati...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-11-01 00:00:00
abstract::Three widely studied cell lines were used to examine the nature of the G1 arrest induced in human tumor cells by ionizing radiation and its relation to p53 status. Cell lines MCF-7 and RKO express wild-type p53, whereas HT29 expresses mutant p53. Exponentially growing cells were irradiated with 6 Gy, and the progressi...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-05-01 00:00:00
abstract::The lethal and bone marrow toxicity and antitumor activity of the cis- and trans-2-hydroxylated metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) have been correlated with their relative in vitro alkylating and carbamoylating activities. Both the isomers have considerably greater alkylating activity a...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1978-04-01 00:00:00
abstract::Type beta transforming growth factor-growth inhibitor (TGF beta/GI) causes normal human prokeratinocytes to arrest growth predominantly in the G1 phase of the cell cycle within 48 h after log phase cultures are exposed to the factor in serum-free medium. The growth arrest induced by TGF beta/GI is reversible because t...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-04-01 00:00:00
abstract::Human embryonic lung fibroblasts (F-136-35-56) capable of growing in medium containing DL-homocysteine instead of L-methionine and human acute lymphoblastic leukemia cells (CCRF-HSB-2) with absolute methionine requirement exhibited dose-dependent growth inhibition when semipurified L-methionine-degrading enzyme (L-met...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1980-03-01 00:00:00
abstract::The ability of interleukin-4 (IL-4) to mediate an antitumor response to human gliomas was studied in vivo in nude mice. To allow the effect of IL-4 to be exerted over a relatively short distance and at an optimal concentration, a transfected tumor cell line expressing a high level of IL-4 was used in mixed tumor trans...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1993-07-01 00:00:00
abstract::Strategies to address resistance to platin drugs are greatly needed in human epithelial cancers (e.g., ovarian, head/neck, and lung) where platins are used widely and resistance occurs commonly. We found that upon ΔNp63α overexpression, AKT1 and phospho-AKT1 levels are upregulated in cancer cells. Investigations using...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-10-1481
更新日期:2011-02-01 00:00:00
abstract::We have previously shown that topotecan, a topoisomerase I poison, inhibits hypoxia-inducible factor (HIF)-1alpha protein accumulation by a DNA damage-independent mechanism. Here, we report that daily administration of topotecan inhibits HIF-1alpha protein expression in U251-HRE glioblastoma xenografts. Concomitant wi...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-2116
更新日期:2004-10-01 00:00:00
abstract::Stromal-epithelial interactions and the bioactive molecules produced by these interactions maintain tissue homeostasis and influence carcinogenesis. Bioactive prostaglandins produced by prostaglandin synthases and secreted by the prostate into seminal plasma are thought to support reproduction, but their endogenous ef...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-4439
更新日期:2005-07-15 00:00:00
abstract::To identify CpG islands differentially methylated in pancreatic adenocarcinoma, we used methylated CpG island amplification (MCA) coupled with representational difference analysis. Of 42 CpG islands identified by MCA/representational difference analysis, 7 CpG islands [methylated in carcinoma of the pancreas (MICP)] w...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-12-01 00:00:00
abstract::Tissue survival responses to ionizing radiation are nonlinear with dose, rather yielding tissue-specific descending curves that impede straightforward analysis of biologic effects. Apoptotic cell death often occurs at low doses, while at clinically relevant intermediate doses, double-strand break misrepair yields mito...
journal_title:Cancer research
pub_type: 评论,杂志文章
doi:10.1158/0008-5472.CAN-19-0312
更新日期:2020-03-01 00:00:00
abstract::The clinical utility of cisplatin to treat human malignancies is often limited by the development of drug resistance. We have previously shown that cisplatin-resistant human KB adenocarcinoma cells that are cross-resistant to methotrexate and heavy metals have altered endocytic recycling. In this work, we tracked lipi...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-3436
更新日期:2006-02-15 00:00:00
abstract::Virtually all patients with chronic myelogenous leukemia (CML) express an aberrant protein (p210 Bcr-Abl) that contains NH2-terminal sequences from Bcr fused to COOH-terminal sequences from Abl. In a yeast two-hybrid screen, we have identified TSG101 as a binding partner for Bcr. Because TSG101 is a subunit of the mam...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-0536
更新日期:2006-06-15 00:00:00
abstract::Recent work on a variety of normal and malignant cell lines has shown that induction and secretion of biologically active TGF-beta may occur after exposure to all-trans-retinoic acid (RA), coincident with decreased growth rate and/or differentiation. This study evaluates the expression and regulation of transforming g...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-06-01 00:00:00
abstract::The alkylating agent temozolomide, commonly used in the treatment of malignant glioma, causes cellular cytotoxicity by forming O(6)-methylguanine adducts. In this report, we investigated whether temozolomide alters the activity of the transcription factor nuclear factor-kappaB (NF-kappaB). Temozolomide inhibits basal ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-4496
更新日期:2007-07-15 00:00:00
abstract::Although apoptosis and necrosis are morphologically distinct manifestations of cell death, apoptosis and some necroses share common features in the death signaling pathway involving functional steps of death-driving interleukin 1beta-converting enzyme family proteases and anti-cell death protein Bcl-2. One evident phy...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1997-05-15 00:00:00
abstract::E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadheri...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-5167
更新日期:2008-04-01 00:00:00
abstract::Whether oncogenic human papilloma viruses (HPVs) are involved in the pathogenesis of prostate cancers has been a subject of great controversy. To clarify the contradictory results of investigations, with the aim of detecting viral nucleic acids in prostate cancers, we have carried out a comparative quantitation of the...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1999-02-15 00:00:00
abstract::Cytotoxic T lymphocytes can lyse Fc receptor-bearing target cells in vitro in the presence of anti-CD3 antibodies. This "redirected" lysis is not restricted by major histocompatibility antigens nor does it require nominal antigen recognition by the CTL. The efficacy of redirected lysis in vivo was assessed by comparin...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1990-09-15 00:00:00
abstract::Activity increase of the cytosolic isozyme of thymidine kinase (TK) in resected specimens of lung tumor patients would be a useful marker for tumor malignancy and prognosis. In 24 resected cases of malignant lung tumors, the whole enzyme extracts of the tumorous part of the specimens showed that the activities of TK, ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-09-01 00:00:00
abstract::Epigenetic changes in pediatric neuroblastoma may contribute to the aggressive pathophysiology of this disease, but little is known about the basis for such changes. In this study, we examined a role for the DNA methyltransferase DNMT3B, in particular, the truncated isoform DNMT3B7, which is generated frequently in ca...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-12-0886
更新日期:2012-09-15 00:00:00