Our laboratory is involved in two separate projects designed to identify, characterize and clone tumor susceptibility/resistance genes in mouse B cell (plasmacytoma) and skin (squamous cell carcinoma) cancer model systems. In the mouse plasmacytoma system, we have documented that at least 3 genes are involved in determining the susceptibility patterns seen in BALB/cAn mice. Two of these genes, Pctr1 and 2 reside in the mid and distal portions of mouse Chr4, respectively. The Pctr1 region shares linkage homology with human 9p21 and 1p31. The Pctr2 and 3 regions in the mouse also share linkage homology with human Chr 1, abnormalities of which have been documented in a variety of human cancers, including breast, neuroblastoma, melanoma, Burkitt's lymphoma and multiple myeloma. We have conducted a series of tumor induction studies in congenic strains of mice designed to harbor defined intervals of genetic material surrounding the Pctr1 locus from resistant strains of mice on a susceptible background. These studies have allowed us to narrow the genetic interval surrounding the Pctr1 locus and has provided us with the information necessary to create further congenics which are recombinant within these intervals to further partition the critical region of interest. We have mapped the cyclin dependent kinase inhibitors Cdkn2a (p16, p19) and Cdkn2b (p15) within the Pctr1 critical region. We have identified two sequence variants between susceptible and resistant mice. Site directed mutagenesis experiments were performed to construct GST-fusion proteins containing the allelic variants associated with the susceptible strain. These proteins did not inhibit phosphorylation of RB in kinase assays and did not bind to CDK4-CyclinD2 complexes. p16 knockout mice are being bred to resistant congenic strains to further evaluate the role of p16 in plasmacytomageneis. In the Pctr2 region, a series of tumor induction studies coupled with allelotypic analyses of a series of recombinant congenic strains have narrowed the genetic interval harboring the susceptibility/resistance gene to 1-2 cM. The Pctr2 locus was found to act in a codominant fashion in studies of F1 hybrids between resistant and susceptible congenic strains of mice. Phenotypic effects of the Pctr2 locus were evident in delaying the onset of tumorigenesis and reducing tumor incidences. In the skin cancer model, we have examined genetic markers distributed across the genome in progeny from a cross between resistant and susceptible mice to test for associations of susceptibility/resistance patterns with marker alleles. We have found 1 major gene on Chr 5 and evidence for two other genes on Chrs 9, and 11 which are linked to tumor susceptibility. In addition a panel of papillomas and carcinomas induced in F1 hybrid mice have exhibited loss of heterozygosity for markers on Chrs 5 and 9. We have created congenic strains to further confirm the Chr 5 locus.
| Zhang, Shuling; Qian, Xiaolan; Redman, Chanelle et al. (2003) p16 INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB. Oncogene 22:2285-95 |
| Bliskovsky, Valery; Ramsay, Edward S; Scott, John et al. (2003) Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene. Proc Natl Acad Sci U S A 100:14982-7 |
