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Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation.
Greenberg RA, O'Hagan RC, Deng H, Xiao Q, Hann SR, Adams RR, Lichtsteiner S, Chin L, Morin GB, DePinho RA
(1999) Oncogene 18: 1219-26
MeSH Terms: Animals, Bacterial Proteins, Base Sequence, Cell Transformation, Neoplastic, Conserved Sequence, DNA-Binding Proteins, Gene Expression Regulation, Humans, Mice, Molecular Sequence Data, Peptidylprolyl Isomerase, Promoter Regions, Genetic, Protein Biosynthesis, Proteins, Proto-Oncogene Proteins c-myc, RNA, RNA-Directed DNA Polymerase, Rats, Sequence Homology, Nucleic Acid, Telomerase, Transcription, Genetic
Show Abstract · Added March 20, 2014
The telomerase reverse transcriptase component (TERT) is not expressed in most primary somatic human cells and tissues, but is upregulated in the majority of immortalized cell lines and tumors. Here, we identify the c-Myc transcription factor as a direct mediator of telomerase activation in primary human fibroblasts through its ability to specifically induce TERT gene expression. Through the use of a hormone inducible form of c-Myc (c-Myc-ER), we demonstrate that Myc-induced activation of the hTERT promoter requires an evolutionarily conserved E-box and that c-Myc-ER-induced accumulation of hTERT mRNA takes place in the absence of de novo protein synthesis. These findings demonstrate that the TERT gene is a direct transcriptional target of c-Myc. Since telomerase activation frequently correlates with immortalization and telomerase functions to stabilize telomers in cycling cells, we tested whether Myc-induced activation of TERT gene expression represents an important mechanism through which c-Myc acts to immortalize cells. Employing the rat embryo fibroblast cooperation assay, we show that TERT is unable to substitute for c-Myc in the transformation of primary rodent fibroblasts, suggesting that the transforming activities of Myc extend beyond its ability to activate TERT gene expression and hence telomerase activity.
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21 MeSH Terms
Telomerase activity in skeletal sarcomas.
Aue G, Muralidhar B, Schwartz HS, Butler MG
(1998) Ann Surg Oncol 5: 627-34
MeSH Terms: Adolescent, Adult, Aged, Bone Neoplasms, Bone and Bones, Child, Female, Humans, Male, Middle Aged, Osteosarcoma, Polymerase Chain Reaction, Telomerase
Show Abstract · Added March 5, 2014
BACKGROUND - Telomerase is a ribonucleoprotein that adds TTAGGG nucleotide repeats onto the ends of eukaryotic chromosomes to maintain telomere integrity. Somatic cells do not express telomerase and stop dividing when the chromosomal ends are shortened critically after many cell divisions. Immortal cell lines and cancer cells apparently have telomerase activity that contributes to an unlimited number of cell cycles. The purpose of our study is to investigate whether telomerase activity is expressed in primary malignant tumors of the skeletal system when compared to adjacent normal tissue.
METHODS - Fresh tumor and normal tissue was collected from 14 patients (10 males, 4 females; age range, 8 to 76 years) and protein extraction performed. The tumors included seven osteosarcomas (three examined before and after chemotherapy), two chondrosarcomas, two spindle cell tumors, one hemangiopericytoma, one chordoma, and one adamantinoma. Telomerase activity was analyzed by using a highly sensitive polymerase chain reaction (PCR)-based assay (telomere repeat amplification protocol [TRAP]).
RESULTS - Telomerase activity was found in 8 of 14 sarcoma patients (57%) using the TRAP assay. Compared to HeLa cell extract (positive control), telomerase activity in the tumor specimen ranged from 0 (in osteosarcoma) to 11.7% (in hemangiopericytoma). There was variation in the number of telomeric repeats generated by telomerase. At least five telomeric bands (e.g. 50, 56, 62, 68, 74 bp) in a ladder pattern had to be present before telomerase activity was considered positive in our analysis.
CONCLUSIONS - Telomerase activity may be an oncogenic sustaining event helping to maintain the transformed phenotype seen in malignant tumors of the bone. The degree of telomerase activity varies among skeletal malignancies, but was less than that observed in HeLa cells. The majority of osteosarcomas showed no telomerase activity.
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13 MeSH Terms
UICC Study Group on Basic and Clinical Cancer Research: mechanisms of growth factor and hormone insensitivity.
Burger MM, Moses HL
(1997) Int J Cancer 73: 461-3
MeSH Terms: Animals, Apoptosis, Cell Cycle, Cytoskeleton, Drug Resistance, Neoplasm, Growth Substances, Hormones, Humans, Neoplasms, Signal Transduction, Telomerase, Telomere, Transforming Growth Factor beta
Added May 27, 2014
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13 MeSH Terms
Lack of microsatellite instability in giant cell tumor of bone.
Scheiner M, Hedges L, Schwartz HS, Butler MG
(1996) Cancer Genet Cytogenet 88: 35-8
MeSH Terms: Adult, Bone Neoplasms, Carcinoma, Giant Cell, Chromosome Aberrations, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Female, Heterozygote, Humans, Male, Microsatellite Repeats, Middle Aged, Polymerase Chain Reaction, Telomerase, Telomere
Show Abstract · Added March 5, 2014
Microsatellite instability was searched for at six different loci on chromosome arms 5q, 18q, 15q, 17p, 19q, and 11p in 22 patients (12 men and 10 women; average age of 31.8 years, range of 20-55 years) with giant cell tumor of bone (GCT). These loci were chosen because of their use in microsatellite instability studies in other tumors such as colorectal cancer (e.g., 5q, 18q, 17p) or because of the presence of chromosomal abnormalities such as telomeric associations commonly occurring at 19q and 11p termini (thus the reason for including the 19q and 11p termini microsatellites in our study of GCT). No microsatellite instability or loss of heterozygosity were detected when comparing normal and tumor cells from any of the GCT patients. Unlike several other tumors, our study indicates that microsatellite instability does not appear to play a role in the tumorigenesis of GCT although other abnormal cytogenetic, biochemical, and molecular genetics data do exist for this musculoskeletal tumor.
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19 MeSH Terms
Cytogenetic, telomere, and telomerase studies in five surgically managed lumbosacral chordomas.
Butler MG, Dahir GA, Hedges LK, Juliao SF, Sciadini MF, Schwartz HS
(1995) Cancer Genet Cytogenet 85: 51-7
MeSH Terms: Adult, Aged, Blotting, Southern, Chordoma, Chromosome Aberrations, DNA, Neoplasm, Female, Humans, Karyotyping, Lumbosacral Region, Male, Middle Aged, Repetitive Sequences, Nucleic Acid, Spinal Neoplasms, Telomerase, Telomere
Show Abstract · Added March 5, 2014
Lumbosacral chordomas are rare skeletal sarcomas of the spine that originate from the remnant notochord. The understanding of this human cancer is limited to observations of its clinical behavior and its embryonic link. Thus, we performed chromosome and molecular analyses from five surgically harvested chordomas in an effort to document genetic and biochemical abnormalities which might aid in understanding the tumor biology of this understudied neoplasm. Cytogenetic analysis of the five chordomas revealed normal results in four patients and random abnormalities in only one tumor cell in the 100 cells studied from the fifth patient. A repeat telomeric probe (TTAGGG)50 was hybridized to genomic DNA isolated from chordoma cells (and HeLa cells) and digested with HinfI. The tumor DNA was paired with leukocyte DNA from age-matched controls and revealed telomere elongation in four of the four chordoma patients studied with molecular genetic techniques. Conversely, telomere length reduction has been reported during in vitro senescence of human fibroblasts, giant cell tumor of bone, colon cancer, intracranial tumors, childhood leukemia, Wilms tumor, and in HeLa cells. Telomerase activity (telomerase is required to maintain telomere integrity) was also determined by visualizing the extension of radioactive telomeric repeats on DNA sequencing gels. The telomeric fragments were assembled during incubation of the cytoplasmic extract containing telomerase. Telomerase activity was observed in HeLa (positive control and commercially available cell line), giant cell tumor of bone (positive control tumor cells from living patients), and in chordoma cells from one of the two chordoma patients (but to a lesser degree compared with HeLa). As expected, the chordoma patients' fibroblasts exhibited no telomerase activity.
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16 MeSH Terms