Haploinsufficiency of p18(INK4c) sensitizes mice to carcinogen-induced tumorigenesis

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Feng Bai1, Xin-Hai Pei, Virginia L Godfrey

  • 1Lineberger Comprehensive Cancer Center. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.

Molecular and Cellular Biology
|January 31, 2003
PubMed

Insights

The p18 INK4 inhibitor acts as a tumor suppressor. Loss of p18 function accelerates tumor development in mice, indicating its haploinsufficient role in tumor suppression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The INK4 family of inhibitors (cyclin-dependent kinase inhibitors) regulates cell cycle progression by inhibiting cyclin D-dependent kinases CDK4 and CDK6.
  • These inhibitors maintain the growth-suppressive activity of Rb family proteins.
  • Mutations in CDK4 conferring INK4 resistance are linked to human melanoma and various mouse tumors.

Purpose of the Study:

  • To investigate the role of p18 (INK4c) in tumor suppression.
  • To determine if p18 exhibits haploinsufficiency in response to chemical carcinogens.

Main Methods:

  • Targeted deletion of the p18 gene in mice to create null and heterozygous models.
  • Treatment of p18-deficient and heterozygous mice with a chemical carcinogen.
  • Analysis of tumor development rates and genetic alterations in p18 alleles within tumors.

Main Results:

  • Targeted deletion of p18 caused spontaneous pituitary tumors and lymphoma in mice late in life.
  • Carcinogen treatment accelerated tumor development in p18 null and heterozygous mice.
  • The remaining wild-type p18 allele in heterozygous tumors showed no mutations or silencing, confirming haploinsufficiency.

Conclusions:

  • p18 functions as a haploinsufficient tumor suppressor in mice.
  • Loss of p18 accelerates chemically induced tumorigenesis.
  • These findings highlight p18's critical role in preventing tumor development.

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