The Adenovirus E1A oncoprotein has been shown to be an effective tool in the identification of protein factors that regulate fundamental cellular processes such as transcription, RNA processing, DNA replication and cell cycle regulation. Several cellular proteins implicated in growth regulation interact with the transforming region of E1A. These proteins have been found to have apparent molecular weights of 33kD, 60kD, 105kD, 107kD, 107kD, 130kD and 300kD. Four of the above mentioned proteins have now been identified. The 105kD protein (P105-Rb) is the product of the retinoblastoma susceptibility gene, the 107kD protein (p107) is structurally related to p105-Rb and the 60kD protein is the product of the cyclin A gene. In addition, several less abundant proteins appear to associate with E1A; one of these is the cyclin-dependent kinase 2 (cdk2), a 33kD protein that is closely related to the cell cycle regulating kinase cdc2. In this grant the focus will be on a gene recently cloned and characterized by us which encodes the E1A-associated protein, p130. We have demonstrated by sequence analysis that this protein is structurally related to the retinoblastoma protein and to p107. By utilizing the technology and reagents employed in our previous studies, we will undertake a systematic examination of the structure and function of p130, and assess the protein's role in regulating cellular proliferation and neoplastic transformation. The demonstration that p130 interacts with the transforming region of E1A and the fact that p130 is related to pRB suggests that this protein may play an important regulatory role in cell cycle progression. Further, p130, like p105-Rb, may prove to be target for inactivation by transforming viruses or by chromosomal aberrations which occur in a wide spectrum of neoplasm. The goals of this proposal are thus: (1) To prepare immunological reagents that will simplify the study of p130 and to identify new protein species that interact with p130. (2) To analyze p130 at different stages of the cell cycle. (3) To conduct structure/function studies of p130 (4) Genomic organization studies of p130.
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