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  • Title: UBE1L is a retinoid target that triggers PML/RARalpha degradation and apoptosis in acute promyelocytic leukemia.
    Author: Kitareewan S, Pitha-Rowe I, Sekula D, Lowrey CH, Nemeth MJ, Golub TR, Freemantle SJ, Dmitrovsky E.
    Journal: Proc Natl Acad Sci U S A; 2002 Mar 19; 99(6):3806-11. PubMed ID: 11891284.
    Abstract:
    All-trans-retinoic acid (RA) treatment induces remissions in acute promyelocytic leukemia (APL) cases expressing the t(15;17) product, promyelocytic leukemia (PML)/RA receptor alpha (RARalpha). Microarray analyses previously revealed induction of UBE1L (ubiquitin-activating enzyme E1-like) after RA treatment of NB4 APL cells. We report here that this occurs within 3 h in RA-sensitive but not RA-resistant APL cells, implicating UBE1L as a direct retinoid target. A 1.3-kb fragment of the UBE1L promoter was capable of mediating transcriptional response to RA in a retinoid receptor-selective manner. PML/RARalpha, a repressor of RA target genes, abolished this UBE1L promoter activity. A hallmark of retinoid response in APL is the proteasome-dependent PML/RARalpha degradation. UBE1L transfection triggered PML/RARalpha degradation, but transfection of a truncated UBE1L or E1 did not cause this degradation. A tight link was shown between UBE1L induction and PML/RARalpha degradation. Notably, retroviral expression of UBE1L rapidly induced apoptosis in NB4 APL cells, but not in cells lacking PML/RARalpha expression. UBE1L has been implicated directly in retinoid effects in APL and may be targeted for repression by PML/RARalpha. UBE1L is proposed as a direct pharmacological target that overcomes oncogenic effects of PML/RARalpha by triggering its degradation and signaling apoptosis in APL cells.
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