Hemangiosarcomas, medulloblastomas, and other tumors in Ink4c/p53-null mice

Frederique Zindy, Lisa M. Nilsson, Luc Nguyen, Cecile Meunier, Richard J. Smeyne, Jerold E. Rehg, Charles Eberhart, Charles J. Sherr, Martine F. Roussel

Research output: Contribution to journalArticlepeer-review

Abstract

Ink4 proteins inhibit the enzymatic activities of cyclin D-dependent kinases, thereby governing transcriptional programs that depend on the activities of the retinoblastoma protein and other retinoblastoma family members (p107 and p130). Mice lacking Ink4c and p53 spontaneously develop a broad spectrum of neoplasms, usually presenting with multiple tumors of different histological types and dying of cancer by 6 months of age. Whereas thymic lymphomas or pituitary tumors predominate in mice lacking p53 or Ink4c, respectively, animals lacking both genes develop many vascular tumors and also present with medulloblastomas not observed in the parental strains. Unlike p53, loss of the Arf tumor suppressor did not contribute to the appearance of vascular or cerebellar tumors. Vascular tumors ranged in severity from angiomas to hemangiosarcomas, some of which could be transplanted into immunocompromised mice. Intriguingly, loss of Ink4c but maintenance of at least one Ink4d allele was required for formation of medulloblastomas in p53-null mice. In situ hybridization revealed that, in newborn mice, Ink4c is detected in the pia mater and in an adjacent layer of rapidly dividing cells within the cerebellar external granule layer (EGL), whereas Ink4d is primarily expressed in Purkinje neurons. Because the pia mater and Purkinje cells sandwich the cerebellar EGL from which medulloblastomas are presumed to arise, Ink4 proteins might function in a cell-autonomous manner in governing neuronal cell cycle exit as well as in a non-cell-autonomous manner in controlling the production of diffusible mitogens and chemokines that influence postnatal development of the cerebellar EGL.

Original languageEnglish (US)
Pages (from-to)5420-5427
Number of pages8
JournalCancer Research
Volume63
Issue number17
StatePublished - Sep 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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