Retinoblastoma is a malignancy of the eye primarily afflicting young children. This disease has been shown to result from inactivation of both alleles of the retinoblastoma susceptibility gene, Rb. The principal investigator has previously described a line of transgenic mice which develop retinoblastoma via oncogene-mediated inactivation of the Rb gene product, pRb, in retinal cells. These mice provided the first heritable animal model system for retinoblastoma. Studies are proposed to further investigate the mechanism of retinoblastoma formation in these mice. Specifically, the possibility that additional mutational events involving gene rearrangements or oncogene amplification will be addressed, using cell lines derived from primary retinoblastoma tumors in these mice. Additional lines of transgenic mice will be produced in which both pRb and another growth suppressor gene product, p53, are inactivated in specific retinal cells, and these mice will be mated to mice overexpressing pRb in the same retinal cells to test the model that pRb inactivation is sufficient for retinoblastoma formation. Also, mice in which pRb but not p53 is inactivated in tbe retina will be produced, and the incidence of retinoblastoma formation will be compared to that of mice in which both proteins are inactivated, to assess the involvement of p53 in the formation of this tumor. Finally, mice in which both pRb and p53 or only one or the other are inactivated in osteoblasts will be produced to test the role of these proteins in osteosarcoma, a common second tumor in retinoblastoma patients. These studies are designed to evaluate the model that the retina is uniquely susceptible to tumorigenesis in that only pRb inactivation is required, while tumor formation in other tissues requires additional mutation events.
| He, Lihua; Perkins, Guy A; Poblenz, Ann T et al. (2003) Bcl-xL overexpression blocks bax-mediated mitochondrial contact site formation and apoptosis in rod photoreceptors of lead-exposed mice. Proc Natl Acad Sci U S A 100:1022-7 |
| Kato, Y; Windle, J J; Koop, B A et al. (1997) Establishment of an osteocyte-like cell line, MLO-Y4. J Bone Miner Res 12:2014-23 |
| Ghosh-Choudhury, N; Windle, J J; Koop, B A et al. (1996) Immortalized murine osteoblasts derived from BMP 2-T-antigen expressing transgenic mice. Endocrinology 137:331-9 |
| Howes, K A; Ransom, N; Papermaster, D S et al. (1994) Apoptosis or retinoblastoma: alternative fates of photoreceptors expressing the HPV-16 E7 gene in the presence or absence of p53. Genes Dev 8:1300-10 |
| Howes, K A; Lasudry, J G; Albert, D M et al. (1994) Photoreceptor cell tumors in transgenic mice. Invest Ophthalmol Vis Sci 35:342-51 |
