TLK1B is elevated with eIF4E overexpression in breast cancer

Norton, Kathryn S; McClusky, Derek; Sen, Siddhartha; Yu, Herbert; Meschonat, Carol; DeBenedetti, Arrigo; Li, Benjamin D.L.

doi:10.1016/j.jss.2003.08.001

Cited by 23 publications

(17 citation statements)

References 19 publications

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“…2c). This observation indicates that the bFGF-2 5 0 UTR affects the specificity of expression of the reporter gene only at the translational level, likely due to high levels of eIF4E expression in cancer cells consistent with previous studies [23]. However, comparison of luciferase mRNA expression levels in phTUWR-luc-transfected MHCC97-H cells (*2.5) and phTUW-luc-transfected MHCC97-H cells (*5.0) differed significantly from the same comparison in SMMC-7721 cells (almost no change).…”

Section: Achievement Of Specificity Of Gene Expression At Both the Trsupporting

confidence: 91%

Development of Chimeric Gene Regulators for Cancer-specific Gene Therapy with both Transcriptional and Translational Targeting

et al. 2010

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Cancer gene therapy has been of great challenge in achieving maximal high levels of specificity and more rational efficiency in target cancer cell. We herein developed a novel approach for cancer-specific gene therapy using both transcriptional and translational targeting regulation. We integrated the tumor-specific gene promoter of hTERT, the 5'UTR of bFGF-2, the enhancer of woodchuck hepatitis virus post-transcriptional regulatory element (WRE), and/or the 3'UTR of the human EGFR into two major chimeric gene regulators. We found that chimeric gene regulator I (hTERT_5'UTR...WRE_BGHpolyA) enhanced the specificity of expression in hepatocellular carcinoma (HCC) cells up to 300% in total due to increases at both the transcriptional and translational levels but only 120-200% enhancement at the transcriptional level and 120-180% enhancement at the translational level. In addition, chimeric gene regulator II (hTERT_5'UTR...WRE_3'UTR_BGHpolyA) improved the specificity to 550% and also highly strengthened the stability of the mRNA. In vitro cytotoxicity assays demonstrated that HCC cell growth was inhibited by HSV-1 TK expression under the control of both chimeric regulators, with a relative cell viability of approximately 80% for 2 days and approximately 85% for 4 days after transfection, respectively. These observations represent a new approach for highly tumor-specific gene expression and also provide insights into application to cancer gene therapy.

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Section: Achievement Of Specificity Of Gene Expression At Both the Trsupporting

confidence: 91%

Development of Chimeric Gene Regulators for Cancer-specific Gene Therapy with both Transcriptional and Translational Targeting

et al. 2010

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“…We have found that elevated expression of TLK1B did not oncogenically transform MM3MG cells, but the cells became highly resistant to IR or doxorubicin [8]. We have preliminary results that demonstrate that TLK1B is elevated in some breast carcinomas and it is possible that this may result in a disease refractory to treatment [30]. We currently favor a mechanism by which TLK1B protects the cells from DSBs, by promoting repair-coupled chromatin remodeling which depends on the phosphorylation of histone H3 and Asf1.…”

Section: Discussionmentioning

confidence: 99%

The radioresistance kinase TLK1B protects the cells by promoting repair of double strand breaks

et al. 2005

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Background: The mammalian protein kinase TLK1 is a homologue of Tousled, a gene involved in flower development in Arabidopsis thaliana. The function of TLK1 is not well known, although knockout of the gene in Drosophila or expression of a dominant negative mutant in mouse cells causes loss of nuclear divisions and missegregation of chromosomes probably, due to alterations in chromatin remodeling capacity. Overexpression of TLK1B, a spliced variant of the TLK1 mRNA, in a model mouse cell line increases it's resistance to ionizing radiation (IR) or the radiomimetic drug doxorubicin, also likely due to changes in chromatin remodeling. TLK1B is translationally regulated by the availability of the translation factor eIF4E, and its synthesis is activated by IR. The reason for this mechanism of regulation is likely to provide a rapid means of promoting repair of DSBs. TLK1B specifically phosphorylates histone H3 and Asf1, likely resulting in changes in chromatin structure, particularly at double strand breaks (DSB) sites.

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“…Only about 10% of mRNAs with 5′UTRs of sufficient length (>200 nt) and three-dimensional steric hindrance require the assistance of the eIF4E for efficient translation [6]. eIF4E overexpression can selectively affect transport of specific transcripts and up-regulate the translation of a limited pool of mRNAs with long G-C rich 5′-UTRs and complex structure, encoding proteins involved in cellular growth, angiogenesis, survival, tumorigenesis, and metastasis,such as cyclin D1, c-myc, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF-2), matrix metalloprotease 9 (MMP-9) [2,7-9].…”

Section: Introductionmentioning

confidence: 99%

Protein expression of eIF4E and integrin αvβ6 in colon cancer can predict clinical significance, reveal their correlation and imply possible mechanism of interaction

et al. 2014

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BackgroundBoth eukaryotic translation initiation factor 4E (eIF4E) and integrin αvβ6 play an important role in the development and progression of cancer. The aim of this study was to investigate the expression of eIF4E and Integrin αvβ6, their clinical significance as well as the two proteins’ correlation in colonic carcinoma tissues.ResultsThe expression levels of eIF4E and integrin αvβ6 were analyzed in colon cancerous and paraneoplastic tissues of 138 cases via tissue microarray (TMA)- immunohistochemistry. And their clinical significance as well as the two proteins’ correlation was also investigated. The expression of eIF4E was significantly associated with clinical TNM stage (P = 0.009), while T stage (P = 0.011) and TNM stage (P = 0.012) were significantly associated with integrin αvβ6 expression. Moderately weak correlation exists between the two proteins (r =0.299, P <0.001). The survival analysis by Kaplan-Meier and Cox regression model showed that protein expression of high eIF4E and positive integrin αvβ6, as independent prognostic factors (RR = 2.417, P = 0.001 and RR = 2.393, P = 0.001), tended to have a significantly poorer 5-year survival rate (P = 0.013 and 0.025, respectively, the log-rank test).ConclusioneIF4E and Integrin αvβ6 were indicators of tumor’s progression and poor prognosis of patients with colon cancer. And the potential signaling loop involving them may provide a helpful therapeutic target in prevention and treatment of colon cancer.

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TLK1B is elevated with eIF4E overexpression in breast cancer

Cited by 23 publications

References 19 publications

Development of Chimeric Gene Regulators for Cancer-specific Gene Therapy with both Transcriptional and Translational Targeting

Development of Chimeric Gene Regulators for Cancer-specific Gene Therapy with both Transcriptional and Translational Targeting

The radioresistance kinase TLK1B protects the cells by promoting repair of double strand breaks

Protein expression of eIF4E and integrin αvβ6 in colon cancer can predict clinical significance, reveal their correlation and imply possible mechanism of interaction

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