International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Monday 18 November

21:15 - 21:30 HRS

PLASMACYTOMA SUSCEPTIBILITY/RESISTANCE LOCI, PCTR1 AND PCTR2 RESULT FROM COMBINATIONS OF SINGLE NUCLEOTIDE POLYMORPHISMS IN GENES THAT ALTER THEIR EFFICIENCY OF FUNCTION

B Mock
NCI, NIH

Co-Authors: 1) Bliskovski V, 1) Zhang S, 1) Ramsay ES, 1) Shi W, 1) Scott J, 2) Qian X, 2) Lowy DR
Institutions: 1) Laboratory of Genetics, CCR, NCI, NIH, 2) Laboratory of Cellular Oncology, CCR, NCI, NIH

The susceptibility of BALB/c mice to plasmacytomas is a complex genetic trait.  We have identified candidate genes for two of the susceptibility/resistance loci.  Pctr1, was mapped to a region on Chr 4 including Cdkn2a, which encodes p16INK4a and p19ARF.   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, while the two p19ARF alleles displayed similar potencies in both assays.  Recently, we have identified promoter variation which affects p16 expression in BALB/c versus DBA B cells, and have identified a transcription factor which negatively regulates the p16 gene more effectively in BALB/c mice.  Thus, BALB/c p16 has a compound defect that reduces both the level of gene expression and the activity of the protein product. Positional cloning efforts have identified a candidate gene for another susceptibility/resistance modifier, Pctr2.  This locus also encodes an efficiency allele with reduced activity in BALB/c mice.  We conclude that plasmacytomas are a model for human cancers which result from an accumulation of several small defects in efficiency of function, rather than complete loss or gain of function mutations.


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