Efficiency Alleles of the Pctr1 Modifier Locus for Plasmacytoma Susceptibility

SL Zhang, W DuBois, ES Ramsay… - … and cellular biology, 2001 - Taylor & Francis
SL Zhang, W DuBois, ES Ramsay, V Bliskovski, HC Morse III, L Taddesse-Heath, WC Vass…
Molecular and cellular biology, 2001Taylor & Francis
The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a complex genetic
trait involving multiple loci, while DBA/2 and C57BL/6 strains are genetically resistant to the
plasmacytomagenic effects of pristane. In this model system for human B-cell neoplasia, one
of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM)
chromosomal region that included Cdkn2a, which encodes p16INK4a and p19ARF, and the
coding sequences for the BALB/c p16INK4a and p19ARF alleles were found to be …
The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a complex genetic trait involving multiple loci, while DBA/2 and C57BL/6 strains are genetically resistant to the plasmacytomagenic effects of pristane. In this model system for human B-cell neoplasia, one of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM) chromosomal region that includedCdkn2a, which encodes p16INK4a and p19ARF, and the coding sequences for the BALB/c p16INK4a and p19ARF alleles were found to be polymorphic with respect to their resistant Pctr1counterparts in DBA/2 and C57BL/6 mice (45). In the present study, alleles of Pctr1, Cdkn2a, andD4Mit15 from a resistant strain (BALB/cDAG) carrying DBA/2 chromatin were introgressively backcrossed to the susceptible BALB/c strain. The resultant C.DAG-Pctr1 Cdkn2a D4Mit15 congenic was more resistant to plasmacytomagenesis than BALB/c, thus narrowingPctr1 to a 1.5-cM interval. Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2agene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn strain. Biological assays of the p16INK4a and p19ARF alleles from BALB/c and DBA/2 indicated that the BALB/c p16INK4a allele was less active than its DBA/2 counterpart in inducing growth arrest of mouse plasmacytoma cell lines and preventing ras-induced transformation of NIH 3T3 cells, while the two p19ARF alleles displayed similar potencies in both assays. We propose that the BALB/c susceptibility/modifier locus, Pctr1, is an “efficiency” allele of the p16INK4a gene.
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