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Molecular and Cellular Biology, January 2001, p. 310-318, Vol. 21, No. 1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.1.310-318.2001

Efficiency Alleles of the Pctr1 Modifier Locus for Plasmacytoma Susceptibility†

Shuling-L. Zhang,1 Wendy DuBois,1 Edward S. Ramsay,1 Valeri Bliskovski,1 Herbert C. Morse III,2 Leki Taddesse-Heath,2 William C. Vass,3 Ronald A. DePinho,4 and Beverly A. Mock1,*

Laboratory of Genetics1 and Laboratory of Cellular Oncology,3 Division of Basic Sciences, National Cancer Institute, and Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases,2 National Institutes of Health, Bethesda, Maryland 20892, and Department of Adult Oncology, Dana-Farber Cancer Institute, and Departments of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts 021154

Received 10 August 2000/Accepted 27 September 2000

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 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 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.

* Corresponding author. Mailing address: Bldg. 37, Rm. 2B-08, 37 Convent Dr., MSC 4255, NCI, NIH, Bethesda, MD 20892-4255. Phone: (301) 496-2360 or (301) 496-3381. Fax: (301) 402-1031. E-mail: bev{at}helix.nih.gov.

dagger We dedicate this paper to the memory of Richard P. Nordan.

Molecular and Cellular Biology, January 2001, p. 310-318, Vol. 21, No. 1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.1.310-318.2001


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