Dataset Information

The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis.

ABSTRACT: Human telomerase reverse transcriptase (hTERT; the catalytic protein subunit of telomerase) is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding, and other functions. The major splice variant termed ?+?- or ?-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the reverse transcriptase domain but retaining the known RNA-binding motifs. In a breast cancer cell panel, we found that ?-deletion was the hTERT transcript that was most highly expressed. Splicing of this transcript was controlled by the splice regulators SRSF11, HNRNPH2, and HNRNPL, and the ?-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, ?-deletion protein competed for binding to telomerase RNA (hTR/TERC), thereby inhibiting endogenous telomerase activity. Overexpressed ?-deletion protein localized to the nucleus and mitochondria and protected breast cancer cells from cisplatin-induced apoptosis. Our results reveal that a major hTERT splice variant can confer a growth advantage to cancer cells independent of telomere maintenance, suggesting that hTERT makes multiple contributions to cancer pathophysiology.

SUBMITTER: Listerman I

PROVIDER: S-EPMC3643995 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis.

Listerman Imke I Sun Jie J Gazzaniga Francesca S FS Lukas Jason L JL Blackburn Elizabeth H EH

Cancer research 20130422 9

Human telomerase reverse transcriptase (hTERT; the catalytic protein subunit of telomerase) is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding, and other functions. The major splice variant termed α+β- or β-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the revers ...[more]

PMID: 23610451

Similar Datasets

Project description:Although fine-needle aspiration (FNA) biopsy of thyroid nodules is very sensitive in detecting thyroid malignancy, it remains ambiguous in 20-30% of cases. Current biomarkers for thyroid cancer lack either the sensitivity or specificity to substantially address this clinical problem. The aim of this study was to investigate the gene expression patterns of human telomerase reverse transcriptase (hTERT) alternative splice variants in benign and malignant thyroid tumors in an attempt to find a more reliable biomarker in the differential diagnosis of thyroid nodules.One hundred and thirty-three thyroid tumors from eight histopathological tumor types were collected from patients undergoing thyroid surgery at Johns Hopkins Hospital. Gene expression patterns of hTERT alternative splice variants were investigated in the tumors by nested reverse transcriptase-PCR. Telomerase enzyme activity was evaluated in a subset of 16 samples associated with the different hTERT patterns. Association of c-myc expression and hTERT patterns was also examined.Malignant thyroid tumors exhibited a greater proportion of the active full-length hTERT transcript (0.57 +/- 0.15) than inactive splice variants, alpha(-) (0.13 +/- 0.02), or beta(-)/alpha(-)beta(-) deletion transcripts (0.30 +/- 0.11; p < 0.001). The opposite was observed in benign tumors, which exhibited greater proportions of beta(-)/alpha(-)beta(-) deletion transcripts (0.64 +/- 0.08) than either the full-length (0.19 +/- 0.06) or alpha(-) deletion transcripts (0.17 +/- 0.02; p < 0.001). Similar results were observed among a diagnostically challenging subset of 50 thyroid tumors that were suspicious for malignancy on FNA. Further, increased telomerase enzymatic activity was only associated with expression of the full-length hTERT isoform. In contrast, c-myc expression, which has been implicated in hTERT regulation, correlated with overall hTERT transcription without specificity for expression of the full-length isoform.These differences in gene expression patterns of hTERT alternative splice variants may provide a useful adjunct to FNA diagnosis of suspicious thyroid tumors.

Dataset Information

The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis.

Publications

The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets