Telomere dysfunction suppresses multiple endocrine Neoplasia in mice

Ji Hyeon Lee, Miriam Anver, Maria Kost-Alimova, Alexei Protopopov, Ronald A. Depinho, Sushil G. Rane

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Multiple endocrine neoplasia (MEN) syndrome is typified by the occurrence of tumors in two or more hormonal tissues. Whereas the genetics of MEN syndrome is relatively well understood, the tumorigenic mechanisms for these cancers remain relatively obscure. The Cdk4R24C mouse model develops highly penetrant pituitary tumors and endocrine pancreas adenomas, and, as such, this model is appropriate to gain insight into mechanisms underlying MEN. Using this model, here we provide evidence supporting an important role for telomerase in the pathogenesis of MEN. We observed increased aneuploidy in Cdk4R/R fibroblasts along with significantly elevated telomerase activity and telomere length in Cdk4R/R islets and embryonic fibroblasts. To better understand the role of telomerase, we generated Cdk4R24C mice with inactivation of the mTERC locus, which codes for the essential RNA component of the enzyme telomerase (mTERC-/- Cdk4R/R mice). Embryonic fibroblasts and islets derived from mTERC-/- Cdk4R/R mice exhibit reduced telomere length and proliferative capacity. Further, mTERC-/- Cdk4R/R fibroblasts display reduced transformation potential. Importantly, mTERC-/- Cdk4R/R mice display significantly reduced spontaneous tumorigenesis. Strikingly, we observed dramatic suppression of pituitary tumors and endocrine pancreas adenomas in mTERC-/- Cdk4R/R mice. Telomere dysfunction suppressed tumor initiation and increased latency of tumor development while not affecting the progression of established tumors. In summary, these results are suggestive of an important role for telomerase in tumor development in the Cdk4R24C mouse model, specifically in the genesis of tumors in the pituitary and the endocrine pancreas.

Original languageEnglish (US)
Pages (from-to)306-319
Number of pages14
JournalGenes and Cancer
Volume5
Issue number9-10
StatePublished - Jan 1 2014

Keywords

  • Endocrine neoplasia
  • Islets
  • Pancreas
  • Pituitary
  • Telomerase

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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