The natural anti-tumor compound Celastrol targets a Myb-C/EBPβ-p300 transcriptional module implicated in myeloid gene expression.
The natural anti-tumor compound Celastrol targets a Myb-C/EBPβ-p300 transcriptional module implicated in myeloid gene expression.
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DOI：
10.1371/journal.pone.0190934
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Klempnauer KH
中科院分区：
文献类型：
--
作者：
Coulibaly A;Haas A;Steinmann S;Jakobs A;Schmidt TJ;Klempnauer KH
Myb是造血祖细胞增殖和分化的关键调节因子，已成为治疗急性白血病的潜在靶点。使用具有稳定整合的Myb诱导型报告基因的骨髓细胞系作为筛选工具，我们先前已经鉴定出具有抗肿瘤活性的天然化合物Celastrol作为有效的Myb抑制剂，其破坏Myb与共激活因子p300的相互作用。我们发现，雷公藤红素抑制急性髓性白血病（AML）细胞的增殖，并在AML的体内模型中降低小鼠的存活率，这表明用小分子抑制剂靶向Myb是可行的，并可能成为AML的治疗方法。最近，我们意识到用于Myb抑制剂筛选的报告系统也对C/EBPβ的抑制有反应，C/EBP β是一种已知在骨髓细胞中与Myb合作的转录因子。通过重新研究雷公藤红素的抑制潜力，我们发现雷公藤红素还通过破坏C/EBPβ与p300的Taz 2结构域的相互作用来强烈抑制C/EBPβ的活性。结合以前的研究，我们的工作揭示了雷公藤红素通过破坏两种转录因子与p300的相互作用而独立地靶向Myb和C/EBPβ。Myb、C/EBPβ和p300在骨髓特异性基因表达中协同作用，并且如最近所示，与AML细胞中所谓的超级增强子相关，这些超级增强子与白血病的维持有关。我们推测雷公藤红素破坏转录Myb-C/EBPβ-p300模块活性的能力可能解释其有希望的抗白血病活性。
Myb is a key regulator of hematopoietic progenitor cell proliferation and differentiation and has emerged as a potential target for the treatment of acute leukemia. Using a myeloid cell line with a stably integrated Myb-inducible reporter gene as a screening tool we have previously identified Celastrol, a natural compound with anti-tumor activity, as a potent Myb inhibitor that disrupts the interaction of Myb with the co-activator p300. We showed that Celastrol inhibits the proliferation of acute myeloid leukemia (AML) cells and prolongs the survival of mice in an in vivo model of AML, demonstrating that targeting Myb with a small-molecule inhibitor is feasible and might have potential as a therapeutic approach against AML. Recently we became aware that the reporter system used for Myb inhibitor screening also responds to inhibition of C/EBPβ, a transcription factor known to cooperate with Myb in myeloid cells. By re-investigating the inhibitory potential of Celastrol we have found that Celastrol also strongly inhibits the activity of C/EBPβ by disrupting its interaction with the Taz2 domain of p300. Together with previous studies our work reveals that Celastrol independently targets Myb and C/EBPβ by disrupting the interaction of both transcription factors with p300. Myb, C/EBPβ and p300 cooperate in myeloid-specific gene expression and, as shown recently, are associated with so-called super-enhancers in AML cells that have been implicated in the maintenance of the leukemia. We hypothesize that the ability of Celastrol to disrupt the activity of a transcriptional Myb-C/EBPβ-p300 module might explain its promising anti-leukemic activity.
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影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
10.5
作者：
KOWENZLEUTZ, E;TWAMLEY, G;LEUTZ, A
通讯作者：
LEUTZ, A
DOI：
10.1073/pnas.88.6.2351
发表时间：
1991-03-01
影响因子：
11.1
作者：
CALABRETTA, B;SIMS, RB;GEWIRTZ, AM
通讯作者：
GEWIRTZ, AM
影响因子：
4.8
作者：
Erickson, RL;Hemati, N;MacDougald, OA
通讯作者：
MacDougald, OA
影响因子：
--
作者：
Aguilar-Morante D;Morales-Garcia JA;Santos A;Perez-Castillo A
通讯作者：
Perez-Castillo A