https://scholars.lib.ntu.edu.tw/handle/123456789/143450
標題: | 探討PML及PML-RARα的小類泛素修飾對Daxx結合之專一性 Specificity of PML and PML-RARα SUMO modification in recruiting Daxx |
作者: | 黃乃家 Huang, Nai-Jia |
關鍵字: | 骨髓性淋巴癌;類色素酸接受體α;死亡結構域相關蛋白;小類泛素修飾蛋白;promyelocytic leukemia (PML);retinoic acid receptor α (RARα);Fas death domain associated protein (Daxx);acute promyelocytic leukemia (APL);small ubiquitin-related | 公開日期: | 2008 | 摘要: | 骨髓性淋巴癌(PML)和類色素酸接受體α(RARα)的融合造成了急性前骨髓性血病(acute promyelocytic leukemia, APL)。類色素酸活性調控下游基因表現影響血球的發育,在APL 細胞中,許多corepressor,像NcoR, SMRT, HDACs 與PML、ARα相互作用而更加抑制了RARα下游基因。此外,最近的研究報導Daxx 與ML 作用會促使更多的co-repressor 結合到PML-RARα上,此作用是藉著PML 上Lys160 site 的小類泛素修飾蛋白(small ubiquitin-like modifier, SUMO)與Daxx的特定胺基酸的SUMO interacting motif (SIM)結合,但Daxx 如何和sumoylatedPML 專一性結合的機制尚未清楚。這篇論文中, 我們藉由不同的方法, 得知PML/PML-RARα 上三個UMO-acceptor Lys(Lys65, Lys160, Lys490)都會與Daxx 相互作用。並探討了PMLPML-RARα上三個Lys residue 受SUMO 修飾的不同,訂出了每一個Lys 所代表修飾位置,並發現這些Lys 受SUMO 修飾是相互影響的,將Lys 突變成Arg,影響其他site 的SUMO 修飾,顯示了PML 上每個Lys 的sumoylation 不是獨立。們還發現了外加與Daxx SUMO interacting motif (SIM)序列一樣的peptide,以有效的回復Daxx 所造成的轉錄抑制,促使RAR 下游基因的表現。將此peptide至來自APL 的細胞:NB4 中,可以有效的降低NB4 不正常的生長速度。綜合言,本篇論文詳加瞭解了PML 及PML-RARα上的sumoylation 和Daxx 的專一性合,更證明了Daxx-SIM 可以當作一個有效抑制APL transformarion 的治療方法。 PML (promyelocytic leukemia gene) fused to retinoic acid receptor α (RARα),erived from the t(15;17) translocation, causes acute promyelocytic leukemia (APL).everal transcriptional corepressors such as NcoR, SMRT and HDACs were shown tossociate with PML-RARα, leading to transcriptional repression. Besides, recent reportsndicated that Daxx could contribute to transcriptional repression ofML/RARα-targeted genes via interacting with SUMO modification at Lys160 of PMLortion. The specificity of how Daxx binds to sumoylated PML has not been wellharacterized. In this study, we used different approaches to show that all threeUMO-acceptor Lys sites of PML and PML-RARα are important for Daxx interaction.n addition, we found that sumoylation level of PML at each Lys acceptor site isffected by each other when individual sumoylation site was mutated, indicating thatML sumoylation at each Lys acceptor is not independent. In addition, we foundxogenous Daxx SUMO-interacting motif (SIM) peptide could reverse Daxx-elicitedepression on PML-RARα-mediated reporter activity and could affect APL celline-NB4 cells proliferation rate. Together, our studies elucidate theumoylation-mediated interaction between PML or PML-RARα and Daxx and providehe evidence that Daxx-SIM peptide may be considered a potential agent for blockingPL-mediated transformation phenotype. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/178815 |
顯示於: | 生化科學研究所 |
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ntu-97-R95b46013-1.pdf | 23.32 kB | Adobe PDF | 檢視/開啟 |
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