Haploinsufficiency of p18INK4c Sensitizes Mice to Carcinogen-Induced Tumorigenesis

AUTOR(ES)

Bai, Feng

FONTE

American Society for Microbiology

RESUMO

The INK4 family of cyclin-dependent kinase (CDK) inhibitors negatively regulates cyclin D-dependent CDK4 and CDK6 and thereby retains the growth-suppressive function of Rb family proteins. Mutations in the CDK4 gene conferring INK4 resistance are associated with familial and sporadic melanoma in humans and result in a wide spectrum of tumors in mice. Whereas loss of function of other INK4 genes in mice leads to little or no tumor development, targeted deletion of p18INK4c causes spontaneous pituitary tumors and lymphoma late in life. Here we show that treatment of p18 null and heterozygous mice with a chemical carcinogen resulted in tumor development at an accelerated rate. The remaining wild-type allele of p18 was neither mutated nor silenced in tumors derived from heterozygotes. Hence, p18 is a haploinsufficient tumor suppressor in mice.

Documentos Relacionados

• Limited overlapping roles of P15INK4b and P18INK4c cell cycle inhibitors in proliferation and tumorigenesis
• CDK inhibitors p18INK4c and p27Kip1 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis
• Carcinogen-induced trans activation of gene expression.
• Carcinogen-induced frameshift mutagenesis in repetitive sequences.
• Carcinogen-Induced Chromosomal Breakage Decreased by Antioxidants