Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression

Lauren D. Wood, Tanya L. Halvorsen, Sonu Dhar, Joseph A. Baur, Raj K. Pandita, Woodring E. Wright, M. Prakash Hande, Gloria Calaf, Tom K. Hei, Fred Levine, Jerry W. Shay, Jean J.Y. Wang, Tej K. Pandita

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by progressive cerebellar degeneration, immunodeficiencies, genomic instability and gonadal atrophy. A-T patients are hypersensitive to ionizing radiation and have an elevated cancer risk. Cells derived from A-T patients require higher levels of serum factors, exhibit cytoskeletal defects and undergo premature senescence in culture. We show here that expression of the catalytic subunit of telomerase (hTERT) in primary A-T patient fibroblasts can rescue the premature senescence phenotype. Ectopic expression of hTERT does not rescue the radiosensitivity or the telomere fusions in A-T fibroblasts. The hTERT + AT cells also retain the characteristic defects in cell-cycle checkpoints, and show increased chromosome damage before and after ionizing radiation. Although A-T patients have an increased susceptibility to cancer, the expression of hTERT in A-T fibroblasts does not stimulate malignant transformation. These immortalized A-T cells provide a more stable cell system to investigate the molecular mechanisms underlying the cellular phenotypes of Ataxia-telangiectasia.

Original languageEnglish (US)
Pages (from-to)278-288
Number of pages11
JournalOncogene
Volume20
Issue number3
DOIs
StatePublished - Jan 18 2001

Bibliographical note

Funding Information:
This work was supported by grants from NIH, Grant NS34746 to TK Pandita, Grant CA43054 to JJY Wang, Grant DK55065 to F Levine and ACS fellowship PF4462 to LD Wood. JW Shay is a senior scholar of the Ellison Medical Foundation.

Keywords

  • ATM
  • Immortal
  • Ionizing radiation
  • Senescence
  • hTERT

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