title: INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform.
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: 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.
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627;
authors.forename: Xiao
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627;
authors.forename: Jorge
authors.initials: J
authors.lastname: Azpurua
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627;
authors.forename: Zhonghe
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Adeline
authors.initials: A
authors.lastname: Augereau
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Zhengdong D
authors.initials: ZD
authors.lastname: Zhang
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627; vera.gorbunova@rochester.edu andrei.seluanov@rochester.edu.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627; vera.gorbunova@rochester.edu andrei.seluanov@rochester.edu.
authors.forename: Andrei
authors.initials: A
authors.lastname: Seluanov
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis* / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D056426:Genetic Loci / Q000502:physiology*; D006801:Humans; D051379:Mice; D019577:Mole Rats; D051381:Rats; D013045:Species Specificity
chemical_list: C493966:CDKN2B protein, human; C417743:Cdkn2a protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16
keywords: INK4; naked mole rat; p15; p16