International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


Dr. Beverly Mock
Center for Cancer Research, NCI, NIH
Bldg. 37, Rm 2B-08
37 Convent Drive, MSC 4255
Bethesda, MD 20892-4255

Co-Authors: 1) Zhang SL, 1) DuBois W, 1) Ramsay ES, 1) Bliskovski V, 2) Morse,III HC, 2) Taddesse-Heath L, 3) Qian X, 3) Vass WC, 4) DePinho RA
Institutions: (1)Laboratory of Genetics, Center for Cancer Research, NCI NIH (3)Laboratory of Cellular Oncology,  DBS, NCI; (2)Laboratory of Immunopathology, NIAID, NIH, 4)Dept. of Adult Oncology, Dana-Farber Cancer Institute, and Depts. of Genetics and Medicine, Harvard Medical School

The susceptibility of BALB/c mice to plasmacytomas is a complex genetic trait.  In this model for human B cell neoplasia, one of the BALB/c susceptibility loci, Pctr1, was mapped to a region including Cdkn2a, which encodes p16INK4a and p19ARF;  the coding sequences for the BALB/c p16 and p19 alleles were found to be polymorphic with respect to their resistant Pctr1 counterparts in DBA/2 and C57BL/6.  We have found that C57BL/6 mice from which both genes of the Cdkn2a locus have been knocked out developed plasma cell tumors over a shorter latency period than the susceptible BALB/cAn strain.  Biological assays of 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 NIH3T3 cells, while the two p19ARF alleles displayed similar potencies in both assays.  The BALB/c and DBA p16INK4a alleles differ at two codons. We have recently identified promoter variation which also affects the level of expression of p16 in BALB/c versus DBA B cells.  Yet another susceptibility/resistance modifier, Pctr2, resides in the distal portion of mouse Chr 4.  Positional cloning efforts have identified a potential candidate gene for this locus which also encodes a defective allele in susceptible mice.

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