UBE1L is a retinoid target that triggers PML/RARalpha degradation and apoptosis in acute promyelocytic leukemia.
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.
Kitareewan
Sutisak
S
Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755, USA. sutisak.kitareewan@dartmouth.edu
Pitha-Rowe
Ian
I
Sekula
David
D
Lowrey
Christopher H
CH
Nemeth
Michael J
MJ
Golub
Todd R
TR
Freemantle
Sarah J
SJ
Dmitrovsky
Ethan
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D044764:Ubiquitin-Activating Enzymes; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000187:drug effects
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; D044764:Ubiquitin-Activating Enzymes