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 Chr 4, respectively. All three of the regions in the mouse share linkage homology with human Chr 1, abnormalities of which have been documented in a variety of human cancers, including breast, neuroblastoma, melanoma and multiple myeloma. During the past year we have completed 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. Initial experiments have revealed an altered transcript of the tumor suppressor gene, p16 in tumor versus normal tissues. We have identified a sequence variant between susceptible and resistant mice and are in the process of designing experiments to test whether it has functional significance. We have also imported p16 knockout mice to further evaluate the role of p16 in plasmacytomagenesis. In the skin cancer model, we have examined 83 genetic markers distributed across the genome in 81 progeny from a cross between resistant and susceptible mice to test for associations of susceptibility/resistance patterns with marker alleles. We have found 3 genes on Chrs 5, 9 and 11 which are linked to tumor susceptibility and are in the process of creating congenic strains to confirm these linkages. Preliminary experiments have shown differences in the level of p16 expression between resistant and susceptible mice.
| 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 |
