Dataset Information

Human telomerase reverse transcriptase (hTERT) is a target gene of ?-catenin in human colorectal tumors.

ABSTRACT: The majority of colorectal cancers (CRCs) are characterized by a dysregulated canonical Wnt-signaling pathway leading to the stabilization and subsequent cellular increase and accumulation of ?-catenin. After translocation into the nucleus, it acts as a transcription factor resulting in the expression of ?-catenin target genes. These resemble most of the hallmarks of cancer except eternal life. The central mediator of this hallmark is hTERT (human telomerase reverse transcriptase). The hTERT gene is regulated, besides others, by the transcription factor c-Myc and, thus, indirectly via ?-catenin as c-Myc is a ?-catenin target gene. Interestingly, the expression patterns of hTERT and ?-catenin, but not c-Myc are overlapping, probably because c-Myc is not only regulated by ?-catenin, but also by many other transcription factors and pathways. Therefore, we argued that hTERT might be a direct target gene of ?-catenin. In this study, we show evidence that ?-catenin directly regulates the expression of the hTERT gene.

SUBMITTER: Jaitner S

PROVIDER: S-EPMC3466531 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Human telomerase reverse transcriptase (hTERT) is a target gene of β-catenin in human colorectal tumors.

Jaitner Stefanie S Reiche Jana A JA Schäffauer Achim J AJ Hiendlmeyer Elke E Herbst Hermann H Brabletz Thomas T Kirchner Thomas T Jung Andreas A

Cell cycle (Georgetown, Tex.) 20120816 17

The majority of colorectal cancers (CRCs) are characterized by a dysregulated canonical Wnt-signaling pathway leading to the stabilization and subsequent cellular increase and accumulation of β-catenin. After translocation into the nucleus, it acts as a transcription factor resulting in the expression of β-catenin target genes. These resemble most of the hallmarks of cancer except eternal life. The central mediator of this hallmark is hTERT (human telomerase reverse transcriptase). The hTERT gen ...[more]

PMID: 22894902

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Project description:BackgroundTelomerase is a reverse transcriptase that maintains the telomeres of linear chromosomes and preserves genomic integrity. The core components are a catalytic protein subunit, the telomerase reverse transcriptase (TERT), and an RNA subunit, the telomerase RNA (TR). Telomerase is unique in its ability to catalyze processive DNA synthesis, which is facilitated by telomere-specific DNA-binding domains in TERT called anchor sites. A conserved glutamine residue in the TERT N-terminus is important for anchor site interactions in lower eukaryotes. The significance of this residue in higher eukaryotes, however, has not been investigated.Methodology/principal findingsTo understand the significance of this residue in higher eukaryotes, we performed site-directed mutagenesis on human TERT (hTERT) Q169 to create neutral (Q169A), conservative (Q169N), and non-conservative (Q169D) mutant proteins. We show that these mutations severely compromise telomerase activity in vitro and in vivo. The functional defects are not due to abrogated interactions with hTR or telomeric ssDNA. However, substitution of hTERT Q169 dramatically impaired the ability of telomerase to incorporate nucleotides at the second position of the template. Furthermore, Q169 mutagenesis altered the relative strength of hTERT-telomeric ssDNA interactions, which identifies Q169 as a novel residue in hTERT required for optimal primer binding. Proteolysis experiments indicate that Q169 substitution alters the protease-sensitivity of the hTERT N-terminus, indicating that a conformational change in this region of hTERT is likely critical for catalytic function.Conclusions/significanceWe provide the first detailed evidence regarding the biochemical and cellular roles of an evolutionarily-conserved Gln residue in higher eukaryotes. Collectively, our results indicate that Q169 is needed to maintain the hTERT N-terminus in a conformation that is necessary for optimal enzyme-primer interactions and nucleotide incorporation. We show that Q169 is critical for the structure and function of human telomerase, thereby identifying a novel residue in hTERT that may be amenable to therapeutic intervention.

Dataset Information

Human telomerase reverse transcriptase (hTERT) is a target gene of ?-catenin in human colorectal tumors.

Publications

Human telomerase reverse transcriptase (hTERT) is a target gene of β-catenin in human colorectal tumors.

Similar Datasets

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