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INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform
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Edité par CCSD ; National Academy of Sciences -
International audience. 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: p15 INK4b , p16 INK4a , and ARF (alternate reading frame). Although p15 INK4b has its own ORF, p16 INK4a 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 p15 INK4b exon 1 joined to p16 INK4a exons 2 and 3. We have named this isoform pALT INK4a/b (for alternative splicing). We show that pALT INK4a/b is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALT INK4a/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, pALT INK4a/b has stronger ability to induce cell-cycle arrest than either p15 INK4b or p16 INK4a . We hypothesize that the presence of the fourth product, pALT INK4a/b of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species.
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