INK4d-deficient mice are fertile despite testicular atrophy

Frederique Zindy, Jan Van Deursen, Gerard Grosveld, Charles J. Sherr, Martine F. Roussel

Research output: Contribution to journalArticle

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Abstract

The INK4 family of cyclin-dependent kinase (CDK) inhibitors includes four 15- to 19-kDa polypeptides (p16(INK4a), p15(INK4b), p18(INK4c), and p19(INK4d) that bind to CDK4 and CDK6. By disrupting cyclin D-dependent holoenzymes, INK4 proteins prevent phosphorylation of the retinoblastoma protein and block entry into the DNA-synthetic phase of the cell division cycle. The founding family member, p16(INK4a), is a potent tumor suppressor in humans, whereas involvement, if any, of other INK4 proteins in tumor surveillance is less well documented. INK4c and INK4d are expressed during mouse embryogenesis in stereotypic tissue-specific patterns and are also detected, together with INK4b, in tissues of young mice. INK4a is expressed neither before birth nor at readily appreciable levels in young animals, but its increased expression later in life suggests that it plays some checkpoint function in response to cell stress, genotoxic damage, or aging per se. We used targeted gene disruption to generate mice lacking INK4d. These animals developed into adulthood, had a normal life span, and did not spontaneously develop tumors. Tumors did not arise at increased frequency in animals neonatally exposed to ionizing radiation or the carcinogen dimethylbenzanthrene. Mouse embryo fibroblasts, bone marrow-derived macrophages, and lymphoid T and B cells isolated from these animals proliferated normally and displayed typical lineage-specific differentiation markers. Males exhibited marked testicular atrophy associated with increased apoptosis of germ cells, although they remained fertile. The absence of tumors in INK4d-deficient animals demonstrates that, unlike INK4a, INK4d is not a tumor suppressor but is instead involved in spermatogenesis.

Original languageEnglish (US)
Pages (from-to)372-378
Number of pages7
JournalMolecular and Cellular Biology
Volume20
Issue number1
StatePublished - Jan 2000
Externally publishedYes

Fingerprint

Atrophy
Neoplasms
Cyclin-Dependent Kinase Inhibitor Proteins
Cyclin D
Artificial Cells
Retinoblastoma Protein
Holoenzymes
Differentiation Antigens
Spermatogenesis
Ionizing Radiation
Germ Cells
Carcinogens
DNA Damage
Embryonic Development
Cell Cycle
Proteins
B-Lymphocytes
Embryonic Structures
Fibroblasts
Macrophages

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Zindy, F., Van Deursen, J., Grosveld, G., Sherr, C. J., & Roussel, M. F. (2000). INK4d-deficient mice are fertile despite testicular atrophy. Molecular and Cellular Biology, 20(1), 372-378.

INK4d-deficient mice are fertile despite testicular atrophy. / Zindy, Frederique; Van Deursen, Jan; Grosveld, Gerard; Sherr, Charles J.; Roussel, Martine F.

In: Molecular and Cellular Biology, Vol. 20, No. 1, 01.2000, p. 372-378.

Research output: Contribution to journalArticle

Zindy, F, Van Deursen, J, Grosveld, G, Sherr, CJ & Roussel, MF 2000, 'INK4d-deficient mice are fertile despite testicular atrophy', Molecular and Cellular Biology, vol. 20, no. 1, pp. 372-378.
Zindy F, Van Deursen J, Grosveld G, Sherr CJ, Roussel MF. INK4d-deficient mice are fertile despite testicular atrophy. Molecular and Cellular Biology. 2000 Jan;20(1):372-378.
Zindy, Frederique ; Van Deursen, Jan ; Grosveld, Gerard ; Sherr, Charles J. ; Roussel, Martine F. / INK4d-deficient mice are fertile despite testicular atrophy. In: Molecular and Cellular Biology. 2000 ; Vol. 20, No. 1. pp. 372-378.
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