INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform

Xiao Tian, Jorge Azpurua, Zhonghe Ke, Adeline Augereau, Zhengdong D. Zhang, Jan Vijg, Vadim N. Gladyshev, Vera Gorbunova, Andrei Seluanov

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

The naked mole rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the naked mole rat is mediated by the extracellular matrix component hyaluronan of very high molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of naked mole rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15INK4b, p16INK4a, and ARF (alternate reading frame). Although p15INK4b has its own ORF, p16INK4a and ARF share common second and third exons with alternative reading frames. Here, we show that, in the naked mole rat, the INK4a/b locus encodes an additional product that consists of p15INK4b exon 1 joined to p16INK4a exons 2 and 3. We have named this isoform pALTINK4a/b (for alternative splicing). We show that pALTINK4a/b is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALTINK4a/b expression is induced during early contact inhibition and upon a variety of stresses such as UV, gamma irradiation-induced senescence, loss of substrate attachment, and expression of oncogenes. When overexpressed in naked mole rat or human cells, pALTINK4a/b has stronger ability to induce cell-cycle arrest than either p15INK4b or p16INK4a. We hypothesize that the presence of the fourth product, pALTINK4a/b of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species.

Original languageEnglish (US)
Pages (from-to)1053-1058
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number4
DOIs
StatePublished - Jan 27 2015

Keywords

  • INK4
  • Naked mole rat
  • p15
  • p16

ASJC Scopus subject areas

  • General

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