The p107 protein was originally identified through its interaction with the adenovirus E1A oncoprotein. A number of observations have suggested that p107 plays an important role in growth regulation. These observations include: (1) the regions of E1A 's growth regulating abilities; (2) cloning and sequencing of p107 showed that it was structurally related to the retinoblastoma gene product, perhaps the best characterized tumor suppressor gene product; (3) in cells without E1A, p107 binds to the E2F transcription factor and inhibits its ability to act as a transcriptional transactivator. E2F participates in the temporal regulation of many genes that are involved in proliferation including c-myc, B-myb, DHFR, DNA po lymerase-alpha, and cdc2; (4) expression of p107 in sensitive cells causes growth arrest in the G1 phase of the cell cycle. In all of these cases, it appears that p107 acts as a negative regulator of proliferation. In mammalian systems, analyzing the biological function of proteins that act as negative regulators of proliferation has been particularly difficult. However, a useful method to study the function of these proteins in vivo has been particularly difficult. However, a useful method to study the function of these proteins in vivo has been to prepare mouse strains with germline mutations that block the synthesis of the particular protein. Breeding these mice allows the examination of the phenotype of mice that lack the negative regulatory functions of these proteins and helps determine the physiological roles of these proteins. This strategy has proven to be particularly powerful in the analysis of other negative regulators including p53, pRB, WT-1, and APC. Recently, we have succeeded in establishing germ line transmission of a p107-null allele (p107-). The construction of a p107(-) allele provides the first opportunity to examine the biological consequences of inactivating p107 mutations. The overall objective of this work are to examine the physiological effects of loosing the function of p107. Our immediate goals center on three objectives. First, we wish to determine the phenotype of mice that carry inactivating p107 mutations. The p107(+/-) heterozygous mice will be examined during their normal life span for any pathology. We will try to make p107 null mice (p107-/-) by breeding the heterozygous mice. Second, we will breed the heterozygote p107(+/-) mice and, if available, the homozygous p107(-/-) mice with Rb(+/-) mice. The Rb(+/-) mice characteristically develop pituitary tumors beginning about 6 to 0 months of age. This pathology provides a recognizable benchmark to test for synergism between these related proteins. Third, we will prepare and analyze cell lines from mice with heterozygous and homozygous p107.
Showing the most recent 10 out of 52 publications
