Viral jun oncogene serves as a suppressor of phorbol ester TPA induced tumor cell invasion and stromelysin gene expression
Carcinogenesis in the mouse skin is a multistep process involving initiation, promotion, and progression. In order for the benign papilloma cells that have been initiated and promoted to become malignant, genetic alterations are believed to be involved. The viral jun (v-jun) oncogene encodes a transcription factor that can participate in the transactivation of genes through the AP-1 complex. Evidence indicates that the ability of v-jun to transform cells and stimulate transcription depends on the cell type. The question that I have attempted to answer in my dissertation studies is whether expression of the v-jun gene in benign tumor forming mouse keratinocytes that already express an activated c-rasᴴᵃ oncogene would cause malignant progression. Our results showed that the v-jun transfection did not result in malignant progression; instead, we made the unexpected observation that the ability of these cells to invade reconstituted basement membrane matrix (in vitro) in response to the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was suppressed. This phenomenon could partially be explained by the suppression of the induction by phorbol ester of expression of the metalloproteinase, stromelysin (transin). Of interest was the finding that TPA induction of other cellular genes known to be regulated by AP-1 was not inhibited in the benign tumor cells expressing v-jun. The suppressor activity shown by v-jun is different than that of other tumor suppressor genes in that it appears to be specific for the process of tumor invasion. A potential implication of this unexpected finding is that it may provide insight on how to develop cancer therapeutic strategies that can specifically inhibit tumor invasion. I have constructed a set of cassette cloning vectors that can be used for rapid adaptation of DNA restriction fragments. In addition, I have formulated a new model with regards to the mechanism of function for the 70 kDa family of heat shock proteins (hsp 70). This model proposes that hsp 70 serves as a cross-linker molecule between many cellular proteins and the cytoskeletal matrix, and this model may have significant implications on many cellular processes.
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