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      PITX1 protein interacts with ZCCHC10 to regulate hTERT mRNA transcription

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          Abstract

          Telomerase is a ribonucleoprotein ribonucleic enzyme that is essential for cellular immortalization via elongation of telomere repeat sequences at the end of chromosomes. Human telomerase reverse transcriptase ( hTERT), the catalytic subunit of telomerase holoenzyme, is a key regulator of telomerase activity. Telomerase activity, which has been detected in the majority of cancer cells, is accompanied by hTERT expression, suggesting that this enzyme activity contributes to an unlimited replication potential of cancer cells via regulation of telomere length. Thus, hTERT is an attractive target for cancer-specific treatments. We previously reported that pared-like homeodomain 1 ( PITX1) is a negative regulator of hTERT through direct binding to the hTERT promoter. However, the mechanism by which the function of PITX1 contributes to transcriptional silencing of the hTERT gene remains to be clarified. Here, we show that PITX1 and zinc finger CCHC-type containing 10 (ZCCHC10) proteins cooperate to facilitate the transcriptional regulation of the hTERT gene by functional studies via FLAG pull-down assay. Co-expression of PITX1 and ZCCHC10 resulted in inhibition of hTERT transcription, in melanoma cell lines, whereas mutate-deletion of homeodomain in PITX1 that interact with ZCCHC10 did not induce similar phenotypes. In addition, ZCCHC10 expression levels showed marked decrease in the majority of melanoma cell lines and tissues. Taken together, these results suggest that ZCCHC10-PITX1 complex is the functional unit that suppresses hTERT transcription, and may play a crucial role as a novel tumor suppressor complex.

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          Most cited references43

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          Extension of life-span by introduction of telomerase into normal human cells.

          Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced straining for beta-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful state could have important applications in research and medicine.
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            Telomeres and human disease: ageing, cancer and beyond.

            Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.
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              Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells.

              Telomerase activity controls telomere length and plays a pivotal role in stem cells, aging, and cancer. Here, we report a molecular link between Wnt/β-catenin signaling and the expression of the telomerase subunit Tert. β-Catenin-deficient mouse embryonic stem (ES) cells have short telomeres; conversely, ES cell expressing an activated form of β-catenin (β-cat(ΔEx3/+)) have long telomeres. We show that β-catenin regulates Tert expression through the interaction with Klf4, a core component of the pluripotency transcriptional network. β-Catenin binds to the Tert promoter in a mouse intestinal tumor model and in human carcinoma cells. We uncover a previously unknown link between the stem cell and oncogenic potential whereby β-catenin regulates Tert expression, and thereby telomere length, which could be critical in human regenerative therapy and cancer.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: MethodologyRole: SoftwareRole: Writing – review & editing
                Role: Formal analysis
                Role: Formal analysis
                Role: Formal analysis
                Role: Data curationRole: Formal analysisRole: ResourcesRole: Writing – review & editing
                Role: MethodologyRole: SoftwareRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 August 2019
                2019
                : 14
                : 8
                : e0217605
                Affiliations
                [1 ] Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Tottori, Japan
                [2 ] Chromosome Engineering Research Center, Tottori University, Yonago, Tottori, Japan
                [3 ] Department of Immunology, Graduate School of Medicine, Osaka City University, Asahi-machi, Abeno-ku, Osaka, Japan
                [4 ] Division of Pathological Biochemistry, School of Life Science, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan
                [5 ] Department of Molecular Pathology, Graduate School of Medicine, Osaka City University, Asahi-machi, Abeno-ku, Osaka, Japan
                Universitat des Saarlandes, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-19-13571
                10.1371/journal.pone.0217605
                6690549
                31404068
                b03a4931-a54a-4b11-b77d-8fd8c577b7c6
                © 2019 Ohira et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 May 2019
                : 29 July 2019
                Page count
                Figures: 7, Tables: 1, Pages: 21
                Funding
                Funded by: Japan Society for the Promotion of Science (JSPS)
                Award ID: Grant-in-Aid for Young Scientists (Start-up) Grant Number 15H06414
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science (JSPS)
                Award ID: Early-Career Scientists Grant Number 18K16030
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science (JSPS)
                Award ID: Grant-in-Aid for Scientific Research (C) Grant Number 15K08304
                This work was supported by Japan Society for the Promotion of Science (JSPS), a Grant-in-Aid for Young Scientists (Start-up) Grant Number 15H06414, Early-Career Scientists Grant Number 18K16030, and Grant-in-Aid for Scientific Research (C) Grant Number 15K08304. This research was partly performed at the Tottori Bio Frontier managed by Tottori prefecture. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Research and Analysis Methods
                Precipitation Techniques
                Immunoprecipitation
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Cloning
                Research and Analysis Methods
                Molecular Biology Techniques
                Cloning
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Domains
                Homeobox
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Transcriptional Control
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Transcription Factors
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Transcription Factors
                Biology and Life Sciences
                Biochemistry
                Proteins
                Regulatory Proteins
                Transcription Factors
                Research and Analysis Methods
                Biological Cultures
                Cell Cultures
                Cultured Tumor Cells
                Melanoma Cells
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Domains
                Biology and Life Sciences
                Genetics
                Gene Expression
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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                Uncategorized

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