NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association.
NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association.
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DOI：
10.1038/onc.2009.236
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发表时间：
2009-10-29
期刊：
影响因子：
8
通讯作者：
Ye, K.
中科院分区：
文献类型：
--
作者：
Chan, C. B.;Liu, X.;Jang, S-W;Hsu, S. I-H;Williams, I.;Kang, S.;Chen, J.;Ye, K.
细胞周期蛋白A1是白血病进展所必需的，其表达受到腺泡（一种核斑点蛋白）的严格调控。然而，腺泡如何介导细胞周期蛋白A1表达的分子机制仍然是难以捉摸的。在这里，我们表明，转录辅抑制因子CtBP 2直接结合腺泡，这是由神经生长因子调节，抑制其刺激作用的细胞周期蛋白A1，但不是细胞周期蛋白A2在白血病的表达。神经营养受体TrkA的同源配体NGF通过Akt触发腺泡磷酸化促进CtBP 2与腺泡之间的相互作用。CtBP 2的过表达减少了细胞周期蛋白A1的转录，而CtBP 2的缺失则消除了NGF对细胞周期蛋白A1表达的抑制作用。引人注目的是，藤黄酰胺，一种新发现的TrkA激动剂，有效地抑制细胞周期蛋白A1的表达，从而阻断K562细胞增殖。此外，藤黄酰胺改善K562细胞接种裸鼠的白血病进展。因此，神经生长因子下调细胞周期蛋白A1的表达，通过升级CtBP 2/腺泡复合物的形成，和藤黄酰胺可能是有用的人类白血病治疗。
Cyclin A1 is essential for leukemia progression, and its expression is tightly regulated by acinus, a nuclear speckle protein. However, the molecular mechanism of how acinus mediates cyclin A1 expression remains elusive. Here we show that transcription corepressor CtBP2 directly binds acinus, which is regulated by NGF, inhibiting its stimulatory effect on cyclin A1 but not cyclin A2 expression in leukemia. NGF, a cognate ligand for the neurotrophic receptor TrkA, promotes the interaction between CtBP2 and acinus through triggering acinus phosphorylation by Akt. Overexpression of CtBP2 diminishes cyclin A1 transcription, whereas depletion of CtBP2 abolishes NGF’s suppressive effect on cyclin A1 expression. Strikingly, gambogic amide, a newly identified TrkA agonist, potently represses cyclin A1 expression, thus blocking K562 cell proliferation. Moreover, gambogic amide ameliorates the leukemia progression in K562 cells inoculated nude mice. Hence, NGF down-regulates cyclin A1 expression through escalating CtBP2/acinus complex formation, and gambogic amide might be useful for human leukemia treatment.
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影响因子：
8
作者：
Ji, P;Agrawal, S;Müller-Tidow, C
通讯作者：
Müller-Tidow, C
影响因子：
4.3
作者：
Liu, Wei;Guo, Qing-Long;Yuan, Sheng-Tao
通讯作者：
Yuan, Sheng-Tao
影响因子：
2.9
作者：
DEWECK, Z;PANDE, J;KAGI, JHR
通讯作者：
KAGI, JHR
影响因子：
20.3
作者：
Li, Zhixiong;Beutel, Gernot;Baum, Christopher
通讯作者：
Baum, Christopher
DOI：
10.1073/pnas.1633591100
发表时间：
2003-08-05
影响因子：
11.1
作者：
Fjeld, CC;Birdsong, WT;Goodman, RH
通讯作者：
Goodman, RH