The Role and Regulation of P19Arf During Ab-MLV Transformation
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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Changes in p19Arf Localization Accompany Crisis
27 cell line Ab-MLV transformation Abelson disease activation of p53 amino acids analyzed animals antibodies apoptosis apoptotic Arf expression Arf null Arf proteins binding bone marrow C-terminus carboxyl terminus cDNA cells expressing cytoplasm detected Dmp1 encoded examined exon experiments express p19Arf expression of p19Arf Figure form of p19Arf full-length Mdm2 function gene harvested heterozygous human cancers immunofluorescence incubated inhibit transformation Ink/Arf Ink4a Ink4a/Arf locus Ink4a/Arf null interaction kinase levels of p19Arf localization of p19Arf lysates MEFs mice molecule mutation nucleolar localization nucleolar p19Arf nucleolus Nucleophosmin nucleoplasm null mice oncogenic p19Arf expression p19Arf protein p53 pathway pre-B cells primary transformants Radfar real time PCR region retain wild type revealed role Rosenberg samples sequences SH2 domain shown signaling staining suggesting transformation by Ab-MLV tumor cells tumor development tumor suppressor ubiquitin ubiquitin ligase uninfected v-Abl v-Abl protein variants virus vitro vivo Western blot wild type mice wild type p53