Activation of the cellular DNA replication machinery is central to the process of neoplastic transformation. The proliferating cell nuclear antigen (PCNA) functions in DNA replication as an auxiliary factor in leading strand synthesis. In accord with this function, the cellular PCNA level increases in response to mitogenic agents such as growth factors and viral oncogenes, including the 12S transforming product of the adenovirus E1A oncogene. The goal of this project is to explore the relationship between gene activation and oncogenic transformation by elucidating the E1A-mediated induction of PCNA gene expression. The approach consists of identifying the regions of the E1A protein that are required for induction of PCNA transcription by use of cotransfection assays. These mapping results will be correlated with known functions of the E1A proteins, particularly with their ability to bind cellular proteins such as the retinoblastoma susceptibility gene product and p60/cyclin A. To gain further mechanistic insight, the cis-acting E1A- responsive elements of the PCNA promoter will be delineated in the co- transfection assay and the trans-acting factors that mediate the E1A response will be identified by genetic and biochemical approaches. These findings will be extended by examining a variety of cell types of rat and human origin that exhibit both normal and transformed growth properties. The results of these experiments will contribute to an understanding of the mechanism whereby a viral oncoprotein can stimulate the expression of a cellular growth-regulated gene.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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On, Kin Fan; Jaremko, Matt; Stillman, Bruce et al. (2018) A structural view of the initiators for chromosome replication. Curr Opin Struct Biol 53:131-139
Knott, Simon R V; Wagenblast, Elvin; Khan, Showkhin et al. (2018) Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554:378-381
Shamay, Yosi; Shah, Janki; I??k, Mehtap et al. (2018) Quantitative self-assembly prediction yields targeted nanomedicines. Nat Mater 17:361-368
Tramentozzi, Elisa; Ferraro, Paola; Hossain, Manzar et al. (2018) The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592. Cell Cycle 17:1102-1114
Arun, Gayatri; Diermeier, Sarah D; Spector, David L (2018) Therapeutic Targeting of Long Non-Coding RNAs in Cancer. Trends Mol Med 24:257-277
Tarumoto, Yusuke; Lu, Bin; Somerville, Tim D D et al. (2018) LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia. Mol Cell 69:1017-1027.e6
Xu, Yali; Milazzo, Joseph P; Somerville, Tim D D et al. (2018) A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia. Cancer Cell 33:13-28.e8
Huang, Yu-Han; Klingbeil, Olaf; He, Xue-Yan et al. (2018) POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev 32:915-928
Livshits, Geulah; Alonso-Curbelo, Direna; Morris 4th, John P et al. (2018) Arid1a restrains Kras-dependent changes in acinar cell identity. Elife 7:
Tiriac, Hervé; Belleau, Pascal; Engle, Dannielle D et al. (2018) Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8:1112-1129

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