UBE1L is a retinoid target that triggers PML/RARα degradation and apoptosis in acute promyelocytic leukemia
Sutisak Kitareewan,Ian Pitha-Rowe,David Sekula,Christopher H. Lowrey,Michael J. Nemeth,Todd R. Golub,Todd R. Golub,Sarah J. Freemantle,Ethan Dmitrovsky +8 more
TLDR
UBE1L is proposed as a direct pharmacological target that overcomes oncogenic effects of PML/RARα by triggering its degradation and signaling apoptosis in APL cells.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 α (RARα). 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/RARα, a repressor of RA target genes, abolished this UBE1L promoter activity. A hallmark of retinoid response in APL is the proteasome-dependent PML/RARα degradation. UBE1L transfection triggered PML/RARα degradation, but transfection of a truncated UBE1L or E1 did not cause this degradation. A tight link was shown between UBE1L induction and PML/RARα degradation. Notably, retroviral expression of UBE1L rapidly induced apoptosis in NB4 APL cells, but not in cells lacking PML/RARα expression. UBE1L has been implicated directly in retinoid effects in APL and may be targeted for repression by PML/RARα. UBE1L is proposed as a direct pharmacological target that overcomes oncogenic effects of PML/RARα by triggering its degradation and signaling apoptosis in APL cells.read more
Citations
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The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR
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