The Role and Regulation of P19Arf During Ab-MLV Transformation

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ProQuest, 2007 - 204 pages
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To understand the way in which p19Arf affects all aspects of transformation, the ability of the molecule to suppress transformation soon after infection was investigated, and it was found that p19Arf expression can inhibit primary transformation. Despite this result, PCR and immunofluorescence analysis of wild type bone marrow cells infected with v-Abl, revealed that p19Arf is expressed soon after infection. This expression is not sufficient to induce apoptosis, as it is seen in healthy cells. Further analysis of the immunofluorescence images revealed that the localization of p19Arf changes from mostly nucleoplasmic early in transformation to mostly nucleolar during crisis. These data together suggest that the localization of p19Arf is important for the induction of apoptosis in transforming cells. The products of the Ink4a/Arf locus also affect tumor induction in vivo, as Abelson disease was accelerated in Ink4a/Arf and Arf null mice. Tumors obtained from mice infected with Ab-MLV expressed p19 Arf, suggesting that the expression of the protein may not be sufficient for triggering a response by p53. Also, in some cancers, variants of Mdm2 are expressed and enhance tumor development because they have lost the ability to bind p19Arf. Similar variants were found during Ab-MLV transformation and perhaps contribute to p19Arf function. Taken together, the results in this thesis provide further clues in understanding the role and regulation of p19Arf during transformation.

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Cancer Development
Tissue Culture
Changes in p19Arf Localization Accompany Crisis

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