Interspecies hybrids from Xiphophorus fish have been used for decades to investigate genetic determinants of melanoma formation. Genetic and molecular analyses of inheritance of spontaneous and UV-induced melanomas in several Xiphophorus backcross hybrids have resulted in the discoveries of an EGFR-related oncogene - the Xiphophorus melanoma receptor kinase, Xmrk2 - and a melanoma susceptibility gene belonging to the CDKN2 family of cyclin-dependent kinase inhibitors, CDKN2X., which we discovered during the course of the funding of this grant. However, although the genetic evidence implicating this gene in melanoma susceptibility in Xiphophorus BC1 hybrids from particular crosses is strong and compelling, the specific role of this putative cell cycle regulator in tumorigenesis in Xiphophorus remains undefined. Our recent studies have shown that CDKN2X is overexpressed in primary melanomas, and that overexpression correlates with overexpression of other cell cycle regulating genes including cyclin D1 as well as overexpression of the upstream tyrosine receptor kinase, Xmrk2. In this project, we propose to investigate several cell cycle regulating genes in Xiphophorus organisms and cell culture models, including cyclin D1, Rb, and forkhead transcription factors. We will develop approaches and systems that will provide an experimental framework for investigating the cell physiology and biochemistry of melanoma formation in Xiphophorus, thereby providing greater scope for exploitation of this unique experimental melanoma model. We will characterize some of the early cellular and biochemical changes occurring in primary melanoma development. To accomplish this goal, we will (a) determine the relationship(s) between cell cycle regulating components and melanoma development in primary melanomas from Xiphophorus hybrids, (b) characterize the expression of specific cell cycle-regulating genes, at both the RNA and protein levels, in primary melanomas generated from Xiphophorus F1 and BC1 hybrids, at different temporal stages of tumor development; these results will be correlated with pathological descriptions of the tumors in situ, and spatial and temporal descriptions will be synthesized in an attempt to identify how primary melanomas manifest changes in cell cycle regulation as they develop. We will also (c) exploit cell culture models to investigate mechanisms by which Xmrk2 influences the expression of CDKN2X and other cell cycle regulators in cell culture models. ? ?
| Rahn, Jennifer J; Trono, David; Gimenez-Conti, Irma et al. (2009) Etiology of MNU-induced melanomas in Xiphophorus hybrids. Comp Biochem Physiol C Toxicol Pharmacol 149:129-33 |
| Butler, Andrew P; Trono, David; Coletta, Luis Della et al. (2007) Regulation of CDKN2A/B and Retinoblastoma genes in Xiphophorus melanoma. Comp Biochem Physiol C Toxicol Pharmacol 145:145-55 |
| Butler, Andrew P; Trono, David; Beard, Rebecca et al. (2007) Melanoma susceptibility and cell cycle genes in Xiphophorus hybrids. Mol Carcinog 46:685-91 |
| Kazianis, Steven; Khanolkar, Vandeeta A; Nairn, Rodney S et al. (2004) Structural organization, mapping, characterization and evolutionary relationships of CDKN2 gene family members in Xiphophorus fishes. Comp Biochem Physiol C Toxicol Pharmacol 138:291-9 |
| Rudd, Michael D; Johnston, Dennis A; Kazianis, Steven et al. (2003) Cloning and analysis of a FoxO transcription factor from Xiphophorus. Gene 302:31-41 |
| Kazianis, S; Gimenez-Conti, I; Setlow, R B et al. (2001) MNU induction of neoplasia in a platyfish model. Lab Invest 81:1191-8 |
| Kazianis, S; Coletta, L D; Morizot, D C et al. (2000) Overexpression of a fish CDKN2 gene in a hereditary melanoma model. Carcinogenesis 21:599-605 |
| Kazianis, S; Morizot, D C; Coletta, L D et al. (1999) Comparative structure and characterization of a CDKN2 gene in a Xiphophorus fish melanoma model. Oncogene 18:5088-99 |
| Morizot, D C; McEntire, B B; Della Coletta, L et al. (1998) Mapping of tyrosine kinase gene family members in a Xiphophorus melanoma model. Mol Carcinog 22:150-7 |
| McConnell, T J; Godwin, U B; Norton, S F et al. (1998) Identification and mapping of two divergent, unlinked major histocompatibility complex class II B genes in Xiphophorus fishes. Genetics 149:1921-34 |
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