In the past few years, significant progress has been made in understanding the molecular pathology of acute promyelocytic leukemia (APL). Both cell culture and animal models support the suggestion that the PML-RARA fusion protein resulting from the t(15;17) is responsible for the development of APL. However, our studies indicate that loss of function of PML, a growth and transformation suppressor disrupted in APL may also contribute to the pathogenesis of APL. Our major focus during the previous funding period was to understand the biological function of PML. Several new findings have resulted from these studies. (a) PML plays a role in regulating cell cycle progression and apoptosis. These important properties of PML are just beginning to emerge and the molecular mechanism of how PML regulates cell cycle progression and apoptosis is not well understood. (b) Our studies suggest that PML is a substrate of cyclin-dependent kinases, this further supporting a role for PML in cell cycle control. How phosphorylation of PML affects growth suppression and apoptosis is unknown. (c) Our studies provided significant insight into the transcriptional regulatory function of PML. We found that PML represses Sp1-dependent transcription of target genes involved in the G1 to S transition, and that PML represses transactivation of NFkappaB target promoters. (d) PML recruits histone deacetylase and silences transcription of target genes by deacetylation of the promoter. We propose to continue to pursue the following specific aims: (1) to study the mechanism of PML regulation of cell cycle progression. Hypothesis to be tested: PML regulates cell cycle progression by inducing a GI arrest through its effects on transactivation of genes involved in the G1/S checkpoint. (2) To study the molecular basis of PML induced apoptosis. Hypothesis to be tested: PML induces apoptosis by (i) de-repression of the antiapoptotic effects of NFKB; (ii) induced expression of p53; and (iii) functional interaction with Bax. (3) To study PML phosphorylation and the biologic significance. Hypothesis to be tested: Phosphorylation and dephosphorylation of the PML protein play an important role in the regulation of cell cycle progression, apoptosis, and transcription regulation. Studies outlined in this proposal will provide important information toward understanding cell cycle regulation and apoptosis. Results obtained from these studies will further expand our knowledge in understanding the molecular pathology of acute promyelocytic leukemia.
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