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Efficiency alleles of the Pctr1 modifier locus for plasmacytoma susceptibility.

Abstract
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 p16(INK4a) and p19(ARF), and the coding sequences for the BALB/c p16(INK4a) and p19(ARF) alleles were found to be polymorphic with respect to their resistant Pctr1 counterparts in DBA/2 and C57BL/6 mice (45). In the present study, alleles of Pctr1, Cdkn2a, and D4Mit15 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 narrowing Pctr1 to a 1.5-cM interval. Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2a gene 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 p16(INK4a) and p19(ARF) alleles from BALB/c and DBA/2 indicated that the BALB/c p16(INK4a) 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 p19(ARF) alleles displayed similar potencies in both assays. We propose that the BALB/c susceptibility/modifier locus, Pctr1, is an "efficiency" allele of the p16(INK4a) gene.
AuthorsS L Zhang, W DuBois, E S Ramsay, V Bliskovski, H C Morse 3rd, L Taddesse-Heath, W C Vass, R A DePinho, B A Mock
JournalMolecular and cellular biology (Mol Cell Biol) Vol. 21 Issue 1 Pg. 310-8 (Jan 2001) ISSN: 0270-7306 [Print] United States
PMID11113205 (Publication Type: Journal Article)
Chemical References
  • Carrier Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proteins
  • Terpenes
  • Tumor Suppressor Protein p14ARF
  • pristane
Topics
  • 3T3 Cells
  • Alleles
  • Animals
  • Carrier Proteins (genetics)
  • Cell Division
  • Cell Transformation, Neoplastic (chemically induced, genetics, pathology)
  • Chromosome Mapping
  • Cyclin-Dependent Kinase Inhibitor p16
  • Flow Cytometry
  • G1 Phase
  • Genes, p16 (genetics)
  • Genes, ras (genetics)
  • Genetic Predisposition to Disease (genetics)
  • Genetic Variation (genetics)
  • Histocytochemistry
  • Mice
  • Mice, Congenic
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Mice, Knockout
  • Plasmacytoma (chemically induced, genetics, pathology)
  • Proteins (genetics)
  • Terpenes (pharmacology)
  • Tumor Stem Cell Assay
  • Tumor Suppressor Protein p14ARF

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