一种针对烟曲霉素作用模式的化学与遗传学方法。
A chemical and genetic approach to the mode of action of fumagillin.
作者信息
Zhang Yi, Yeh Jing Ruey, Mara Andrew, Ju Rong, Hines John F, Cirone Pasquale, Griesbach Hilary L, Schneider Igor, Slusarski Diane C, Holley Scott A, Crews Craig M
机构信息
Department of Molecular, Cell, and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA.
出版信息
Chem Biol. 2006 Sep;13(9):1001-9. doi: 10.1016/j.chembiol.2006.07.010.
Previous mode of action studies identified methionine aminopeptidase 2 (MetAP-2) as the target of the antiangiogenic natural product fumagillin and its drug candidate analog, TNP-470. We report here that TNP-470-mediated MetAP-2 inhibition blocks noncanonical Wnt signaling, which plays a critical role in development, cell differentiation, and tumorigenesis. Consistent with this finding, antisense MetAP-2 morpholino oligonucleotide injection in zebrafish embryos phenocopies gastrulation defects seen in noncanonical Wnt5 loss-of-function zebrafish mutants. MetAP-2 inhibition or depletion blocks signaling downstream of the Wnt receptor Frizzled, but upstream of Calmodulin-dependent Kinase II, RhoA, and c-Jun N-terminal Kinase. Moreover, we demonstrate that TNP-470 does not block the canonical Wnt/beta-catenin pathway. Thus, TNP-470 selectively regulates noncanonical over canonical Wnt signaling and provides a unique means to explore and dissect the biological systems mediated by these pathways.
先前的作用机制研究确定甲硫氨酸氨肽酶2（MetAP - 2）是抗血管生成天然产物烟曲霉素及其候选药物类似物TNP - 470的作用靶点。我们在此报告，TNP - 470介导的MetAP - 2抑制作用阻断了非经典Wnt信号通路，该信号通路在发育、细胞分化和肿瘤发生中起关键作用。与这一发现一致，在斑马鱼胚胎中注射反义MetAP - 2吗啉代寡核苷酸可模拟非经典Wnt5功能丧失的斑马鱼突变体中出现的原肠胚形成缺陷。MetAP - 2抑制或缺失阻断了Wnt受体卷曲蛋白下游、钙调蛋白依赖性激酶II、RhoA和c - Jun氨基末端激酶上游的信号传导。此外，我们证明TNP - 470不会阻断经典的Wnt/β-连环蛋白信号通路。因此，TNP - 470选择性地调节非经典Wnt信号通路而非经典Wnt信号通路，并为探索和剖析由这些通路介导的生物系统提供了一种独特的手段。
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