Loss of heterozygosity at chromosome 3p correlates with telomerase activity in renal cell carcinoma.

Mehle, Christer; Lindblom, Annika; Ljungberg, Börje; Stenling, Roger; Roos, Göran

doi:10.3892/ijo.13.2.289

Cited by 14 publications

(11 citation statements)

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“…These data suggest that there is a functional telomerase repressor on chromosome 3 and that repression of telomerase activity in tumor-derived cell lines results in progressive telomere shortening and reprogramming of cellular senescence. This work has been confirmed by others (Mehle et al, 1998;Tanaka et al, 1998;Vieten et al, 1998;Cuthbert et al, 1999). The telomerase repressor region on chromosome 3p has been narrowed to 3p12-p21.1 and 3p21.3-p22 (Cuthbert et al, 1999), 3p13-p14.2 (Vieten et al, 1998), 3p14.2-p21.1 (Tanaka et al, 1998), and 3p14.2-p21.2 and 3p24.1-p24.3 (Mehle et al, 1998).…”

Section: Proliferation and Telomerasesupporting

confidence: 68%

Role of telomerase in cellular proliferation and cancer

1999

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Telomerase is a cellular reverse transcriptase that helps to provide genomic stability in highly proliferative normal, immortal, and tumor cells by maintaining the integrity of the chromosome ends, the telomeres. The activity of telomerase is associated with the majority of malignant human cancers. Telomerase or another mechanism for telomere maintenance is required for continuous tumor cell proliferation. Telomerase-positive cells that exit the cell cycle via quiescence downregulate telomerase through a transcriptional repression pathway. In the case of cell cycle exit via terminal differentiation, proteolysis of telomerase may also be involved. In response to mitogenic or growth factor signaling, telomerase-competent quiescent cells reenter the cell cycle and express telomerase activity independent of DNA synthesis. Under normal growth conditions, inhibition of telomerase activity in tumor-derived cells results in continued cell division coupled with telomere shortening, eventually followed by cellular senescence or death. Thus, repression of telomerase activity may be a novel adjuvant therapy for the treatment of human cancer and detection of telomerase activity may be important for cancer diagnostics.

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Section: Proliferation and Telomerasesupporting

confidence: 68%

Role of telomerase in cellular proliferation and cancer

1999

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“…The RNA template is usually 100 to 200 nucleotides long and contains several repeats of C-rich elements. Interestingly, loss of heterozygosity (LOH) at 3p21, the mapped location of MCG10, is associated with an increased telomerase activity in head, neck, and renal carcinomas (55,58). Since MCG10 is a potent poly(C)-binding protein, it is possible that, by binding to the C-rich repeats in the RNA template, MCG10 and MCG10as can sequester the RNA template and inhibit telomere synthesis, thereby suppressing cell proliferation.…”

Section: Resultsmentioning

confidence: 99%

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M

Zhu

Chen

2000

Molecular and Cellular Biology

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p53, a tumor suppressor, inhibits cell proliferation by inducing cellular genes involved in the regulation of the cell cycle. MCG10, a novel cellular p53 target gene, was identified in a cDNA subtraction assay with mRNA isolated from a p53-producing cell line. MCG10 can be induced by wild-type but not mutant p53 and by DNA damage via two potential p53-responsive elements in the promoter of the MCG10 gene. The MCG10 gene contains 10 exons and is located at chromosome 3p21, a region highly susceptible to aberrant chromosomal rearrangements and deletions in human neoplasia. The MCG10 gene locus encodes at least two alternatively spliced transcripts, MCG10 and MCG10as. The MCG10 and MCG10as proteins contain two domains homologous to the heterogeneous nuclear ribonucleoprotein K homology (KH) domain. By generating cell lines that inducibly express either wild-type or mutated forms of MCG10 and MCG10as, we found that MCG10 and MCG10as can suppress cell proliferation by inducing apoptosis and cell cycle arrest in G 2 -M. In addition, we found that MCG10 and MCG10as, through their KH domains, can bind poly(C) and that their RNA-binding activity is necessary for inducing apoptosis and cell cycle arrest. Furthermore, we found that the level of the poly(C) binding MCG10 protein is increased in cells treated with the DNA-damaging agent camptothecin in a p53-dependent manner. These results suggest that the MCG10 RNA-binding protein is a potential mediator of p53 tumor suppression.RNA-binding proteins are a large family of proteins with diverse functions which contain one or more RNA-binding domains (RBDs) and other auxiliary domains for protein-protein interaction and subcellular targeting (22,23,46,65,71,78). Several ribosomal proteins are RNA-binding proteins, for example, S6, S15, and L11, which are necessary for ribosome assembly and may be a target for translational regulation (23,82). Several groups of RNA-binding proteins have been shown to play an important role in alternate splicing, RNA editing, and alternate poly(A) site selection. Among these are the abundant heterogeneous nuclear ribonucleoproteins (hnRNPs), which shuttle between the nucleus and cytoplasm (48,74,82).Three major RNA-binding motifs have been found in hnRNPs, that is, the RBD, arginine/glycine-rich box (RGG), and hnRNP K homology (KH) domain. The consensus RBD structure is composed of 90 to 100 amino acids with a ␤␣␤␤␣␤ secondary structure (9). A majority of hnRNPs, such as A, B, C, D, F, G, and H, contain one or more RBDs, which are necessary for the ability of these hnRNPs in the regulation of splicing, RNA trafficking, and mRNA stability (48, 82). RNAbinding experiments demonstrate that RBD motif proteins can bind RNA with a wide range of affinities and specificities (9). The RGG box is composed of several closely spaced arginineglycine-glycine repeats with a ␤-spiral secondary structure (9). Several hnRNPs contain RGG boxes along with RBD or KH motifs. RNA-binding experiments have demonstrated that the RGG box has a relatively weak RNA-binding ...

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“…In renal cell carcinomas, the presence of at least two genes with regulatory function on the expression of telomerase has been suggested (Mehle et al, 1998). Also, deletion analysis of nonrepressed segregant monochromosome 3 hybrids, in human breast cancer cells, indicated two regions on 3p (3p21.3 -p22 and 3p12 -21.1), where telomerase regulator genes may be located (Cuthbert et al, 1999).…”

mentioning

confidence: 99%

Relationship between 3p deletions and telomerase activity in non-small-cell lung cancer: prognostic implications

et al. 2004

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3p deletions and telomerase reactivation are two of the most frequent events described in relation to non-small-cell lung cancer (NSCLC) pathogenesis. Moreover, a number of genes that map on 3p have been proposed as candidates to tumour-suppressor genes of importance in the lung cancer process. In this work, we analysed deletions at different 3p loci in relationship to telomerase activity in 66 NSCLCs obtained from patients who had suffered potentially curative surgery. Also, we evaluated prognostic implications. DNA samples were analysed for 3p deletions using five different polymorphic human dinucleotide repeat DNA markers (D3S1619 at 3p22.2, D3S3623 at 3p22.1, D3S1260 at 3p21.33, D3S3697 at 3p14.3, and D3S3722 at 3p21.2). Telomerase activity was investigated by a TRAP-based method. Possible correlations between the different molecular markers and distributions of disease-free survival were estimated. Our data revealed a significant correlation between telomerase activity and losses of heterozygosity (LOH) on D3S3697 (P ¼ 0.040), since all of the tumours showing deletion at this locus were positives for telomerase. Moreover, our results revealed clear associations with poor prognosis of patients, in the case of LOH at D3S1260 and D3S3697 (P ¼ 0.005 and 0.005, respectively). According to our data, potential repressors for telomerase may be located in chromosome 3p.

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Loss of heterozygosity at chromosome 3p correlates with telomerase activity in renal cell carcinoma.

Cited by 14 publications

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Role of telomerase in cellular proliferation and cancer

Role of telomerase in cellular proliferation and cancer

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M

Relationship between 3p deletions and telomerase activity in non-small-cell lung cancer: prognostic implications

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Loss of heterozygosity at chromosome 3p correlates with telomerase activity in renal cell carcinoma.

Cited by 14 publications

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Role of telomerase in cellular proliferation and cancer

Role of telomerase in cellular proliferation and cancer

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G2-M

Relationship between 3p deletions and telomerase activity in non-small-cell lung cancer: prognostic implications

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MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M