|Studies in Dr. Siracusa' s laboratory focus on a variety of genes involved in cancer susceptibility. Molecular biology combined with classical genetics serve as powerful approaches to characterize these genes and dissect their effects on tumor formation. |
The agouti (A) gene acts within the microenvironment of the hair follicle to direct melanocyte pigment production, regulating a switch between black and yellow. In addition to coat color, several agouti mutations affect susceptibility to solid tumors, obesity, and diabetes. The agouti locus encodes a secreted growth factor-like protein involved in signal transduction. Resemblance of the agouti protein to the calcium channel toxins produced by snails and spiders suggested novel mechanisms for agouti action. This experimental system is an important model to understand genetic factors involved in cancer susceptibility, melanogenesis, and metabolic disorders. Furthermore, certain agouti mutations can produce a range of phenotypes; we are investigating mechanisms responsible for alterations in phenotype of mice of the same genotype. These studies may reveal factors influencing DNA methylation, chromatin structure, gene expression and ultimately, individual variation.
Dr. Siracusa and her group are working to positionally clone and characterize the gene(s) responsible for the repeated epilation (Er) mutation. The Er mutation affects skin and hair phenotypes, as well as causes papillomas and squamous cell carcinomas. This mutant serves as a model of skin development and skin cancer. This group has also identified the gene responsible for the Tight skin mutation (Tsk) in collaboration with Dr. S. Jimenez (Dept. of Rheumatology). They found that a duplication within the Marfan syndrome gene, Fibrillin 1 (Fbn1), was responsible for novel mutant phenotypes. The Tsk mouse serves as a model for human fibrotic diseases such as scleroderma.
Dr. Siracusa is studying the influence of genetic modifier loci on the incidence of polyp development in colon cancer, in collaboration with Dr. A. Buchberg. They identified the Pla2s gene as a candidate for the Mom1 locus, a gene involved in altering susceptibility to intestinal cancer in mice carrying a mutated Apc gene. Mutations in the human APC gene are responsible for some cases of familial and sporadic colorectal cancers. Studies are in progress to establish the mechanism by which Pla2s prevents intestinal polyp formation as well as to investigate the role of PLA2S in human neoplasia. They are also executing strategies to identify additional modifier loci involved in cancer susceptibility.
Dr. Siracusa's laboratory developed a molecular genetic linkage map of the mouse genome to determine the chromosomal location of any gene through the use of interspecific backcross analyses. They have collaborated with several KCC investigators to map their genes of interest. The map is used for many purposes including identification of mouse models of human disease.
Dr. Siracusa has created the MUSMIRSUS (Mus miRNA susceptibility loci) database to compare the positions of microRNA (miRNA) genes with the positions of solid tumor susceptibility and modifier loci in the mouse. The database and a brief description are available at http://www.kimmelcancercenter.org/siracusa/musmirsus.htm
Keywords: mouse models of disease, cancer susceptibility, skin tumor development and genetics, mammalian genetics, MUSMIRSUS
Siracusa, L.D., Abbott, C.M, Morgan, J.L., Zuberi, A.R., Pomp, D. and Peters, J.: Mouse chromosome 2. mammalian Genome 7: S28-S44, 1997
Pekarsky, Y., Druck. T., Cotticelli, M.G., Ohta, M., Shou, J., Mendrola, J., Montgomery, J.C., Buchberg, A.M., Siracusa, L.D., Manenti, G., Fong, L.Y.Y., Dragani, T.A., Croce, C.M., Huebner, K: The murine Fhit locus: Isolation, characterization and expression in normal and tumor cells. Cancer Research 58: 3401-3408, 1998.
Siracusa, L.D., McGrath, R., Fisher, J.K. and Jimenez, S.A.: The mouse tight skin (Tsk) phenotype is not dependent on the presence of mature T and B lymphocytes. Mammalian Genome 9: 907-909, 1998.
Danielson, K.G., Siracusa, L.D., Donovan, P.J. and Iozzo, R.V.: Decorin, epiphycan and lumican genes are closely linked on murine Chromosome 10 and are deleted in lethal steel mutants. Mammalian Genome 10: 201-203, 1999.
Fernandes, M.J., Finnegan, A.A., Siracusa, L.D., Brenner, C., Iscove, N.N. and Calabretta, B.: Characterization of a novel receptor that maps near the natural killer gene complex: Demonstration of carbohydrate-binding and expression in hematopoietic cells. Cancer Research, in press.
Ghiselli, G., Siracusa, L.D. and Iozzo, R.V.: The murine bamacan gene: Complete cDNA cloning, genomic organization, chromosomal assignment, functional characterization of the promoter and expression. J. Biol. Chem., in press.
Larkin, J., Clayton, M., Sun, B., Perchonock, C.E., Morgan, J.L., Siracusa, L.D. and Feitelson, M.A.: Hepatitis B virus transgenic SCID mouse model of chronic liver disease. Nature Medicine, in press.
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