CDKN2A, THE CYCLIN-DEPENDENT KINASE INHIBITOR ENCODING P16(INK4A) ANDP19(ARF), IS A CANDIDATE FOR THE PLASMACYTOMA SUSCEPTIBILITY LOCUS, PCTR1

Plasma cell tumor induction in mice by pristane is under multigenic co ntrol. BALB/c mice are susceptible to tumor development; whereas DBA/2 mice are resistant, Restriction fragment length polymorphisms between BALB/c and DBA/2 for Cdkn2a(p16) and Cdkn2b (p15), and between BALB/c and Mus spretus for Cdkn2c(p18(INK4C)) were used to position these lo ci with respect to the Pctr1 locus. These cyclin-dependent kinase (CDK ) inhibitors mapped to a 6 cM interval of chromosome 4 between Ifna an d Tall. C.D2-Chr 4 congenic strains harboring DBA/2 alleles associated with the Pctr1 locus contained DBA/2 ''resistant'' alleles of the CDK 4/CDK6 inhibitors p16 and p15. On sequencing p16 and p18 cDNAs, two di fferent allelic variants within ankyrin repeat regions of p16 were fou nd between BALB/c and DBA/2 mice, By using an assay involving PCR ampl ification and restriction enzyme digestion, allelic variants were type d among several inbred strains of mice. One of the variants, G232A, wa s specific to two inbred strains, BALB/cAn and ABP/Le, of mice and occ urred in a highly conserved amino acid in both human and rat p16, When tested with wild-type (DBA/2) p16, both A134C and G232A BALB/c-specif ic variants of p16 were inefficient in their ability to inhibit the ac tivity of cyclin D2/CDK4 in kinase assays with retinoblastoma protein, suggesting this defective, inherited allele plays an important role i n the genetic susceptibility of BALB/c mice for plasmacytoma induction and that p16(INK4a) is a strong candidate for the Pctr1 locus.