Acute promyelocytic leukemia (APL; FAB M3) cells have a balanced translocation t(15;17) (q22;12-21) rearranging the retinoic acid receptor- alpha (RARalpha) and promyelocytic leukemia (PML) genes. Two features distinguish APL: (1) APL cells express PML/RARalpha that results from this translocation and (2) all-transretinoic acid (RA) treatment of APL induces complete clinical remissions. Paradoxically, these responses are linked to PML/RARalpha expression. Prior work from our laboratory and others indicate that PML/RARalpha functions as a dominant-negative transcription factor whose, effects are overcome by pharmacological RA dosages leading to degradation of PML/RARalpha protein. Target genes are activated by RA to signal terminal growth suppression and differentiation. Identification of these target genes is the subject of our current work. A hallmark of the APL differentiation program is the rapid proteolysis of PML/RARalpha by RA via proteasomal degradation. Using microarray analyses, direct evidence was found for an RA inducible mechanism for ubiquitin-dependent PML/RARalpha degradation. A gene cluster prominently induced by RA-treatment of APL cells was that of the ubiquitin-ligase system. A component is UBE1L, an E1-like ubiquitin-activating enzyme. UBE1L induction provides a mechanistic basis for PML/RARalpha degradation by RA. We hypothesize that UBE1L is an RA-target gene leading to PML/RARalpha degradation. This relieves dominant-negative effects of PML/RARalpha and permits differentiation to proceed. We confirmed this by co-transfecting UBE1L with PML/RARalpha. This leads to PML/RARalpha degradation even without RA-treatment. For this competing renewal application of NIH R0-1 CA62275-07, we propose to confirm that UBE1L is a direct retinoid target gene . that triggers PML/RARalpha degradation and overcomes the differentiation block in APL cells through three specific aims. First, to study comprehensively the retinoid regulation of UBE1L in RA sensitive and resistant APL cells and determine whether UBE1L is a direct RA target gene. Second, to conduct mechanistic co-transfection studies to elucidate how UBE1L triggers PML/RARalpha degradation. Third, to establish the in vivo relevancy of these findings by conducting UBE1L stable transfection studies in RA sensitive and resistant APL cells that contain wild-type or mutant PML/RARalpha species. Cellular, biochemical, and molecular genetic techniques are used to investigate mechanisms of RA action, using preclinical experimental models of APL. Through successful completion of these aims, a fuller understanding of APL RA response should derive in this important model for differentiation therapy. These findings are relevant to retinoid-based differentiation therapy of other human malignancies.
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