Kitareewan Sutisak, Pitha-Rowe Ian, Sekula David, Lowrey Christopher H, Nemeth Michael J, Golub Todd R, Freemantle Sarah J, Dmitrovsky Ethan
Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755, USA.
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3806-11. doi: 10.1073/pnas.052011299. Epub 2002 Mar 12.
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.
全反式维甲酸（RA）治疗可使表达t(15;17)产物早幼粒细胞白血病（PML）/维甲酸受体α（RARα）的急性早幼粒细胞白血病（APL）病例获得缓解。先前的微阵列分析显示，用RA处理NB4 APL细胞后会诱导UBE1L（泛素激活酶E1样）的表达。我们在此报告，这种情况在RA敏感的APL细胞中3小时内就会发生，但在RA耐药的APL细胞中则不会，这表明UBE1L是维甲酸的直接靶点。UBE1L启动子的一个1.3 kb片段能够以维甲酸受体选择性的方式介导对RA的转录反应。PML/RARα是RA靶基因的阻遏物，它消除了这种UBE1L启动子活性。APL中维甲酸反应的一个标志是蛋白酶体依赖性的PML/RARα降解。UBE1L转染引发了PML/RARα降解，但截短的UBE1L或E1转染并未导致这种降解。结果显示UBE1L诱导与PML/RARα降解之间存在紧密联系。值得注意的是，UBE1L的逆转录病毒表达在NB4 APL细胞中迅速诱导凋亡，但在缺乏PML/RARα表达的细胞中则不会。UBE1L已被直接证明与APL中的维甲酸作用有关，可能是PML/RARα抑制的靶点。UBE1L被提议作为一个直接的药理学靶点，通过触发其降解并在APL细胞中引发凋亡来克服PML/RARα的致癌作用。
