Daniels, Candelaria Christina, authorQuackenbush, Sandra L., advisor2024-03-132024-03-132008https://hdl.handle.net/10217/237669Walleye dermal sarcoma virus is a complex retrovirus associated with walleye dermal sarcomas (WDS). These sarcomas develop and regress on a seasonal basis, providing a unique model to study mechanisms of tumor development and regression in vertebrates. WDS is experimentally transmissible to walleye with cell-free, regressing tumor homogenates. During the fall, low levels of spliced accessory gene transcripts, A and B, are present in developing tumors suggesting that their encoded proteins, rv-cyclin and Orf B, may play a role in oncogenesis. Infectious virus and high levels of full-length viral RNA and spliced accessory and env transcripts are expressed during tumor regression, the following spring. The three accessory proteins Orf A (rv-cyclin), Orf B, and Orf C function in tumor development and regression. In explanted tumor and mammalian cells stably expressing the 35kDa Orf B protein, Orf B is localized at the cell periphery in structures similar to focal adhesions and along actin stress fibers. Results from these studies demonstrate Orf B interacts directly or in a complex with several cellular proteins important in signal transduction pathways: receptor for activated C kinase (RACK1), protein kinase C alpha (PKCα), Src, phosphatidylinositol-3-kinase (PI3K), and protein phosphatase 2A (PP2A). The cellular proteins BAD, 90kDa ribosomal S6 kinase (p90RSK), PKCα, and protein kinase B (AKT), which are important in controlling apoptosis and/or proliferation, are activated in Orf B-expressing cells. Orf B protects cells from staurosporine-induced apoptosis and induces cell proliferation of Orf B-expressing cells under serum-deprived conditions suggesting a mechanism of action for tumor development. Expression of Orf B induces transformation of NIH3T3 cells in vitro and a PI3K and mTOR inhibitor prevented transformation, providing the first evidence that Orf B induces a transformed phenotype. The regulation of cell signaling pathways is one way in which viruses induce oncogenesis. Orf B ensures the establishment of dermal sarcoma by activating signal transduction pathways that control cell survival and proliferation such as PKC and Akt.born digitaldoctoral dissertationsengCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.oncogenesisOrf bprotein kinase CRACK1retrovirusessignal transductionWDSVwalleye dermal sarcoma virusmicrobiologyvirologyTextPer the terms of a contractual agreement, all use of this item is limited to the non-commercial use of Colorado State University and its authorized users.