Critical roles of Myc-ODC axis in the cellular transformation induced by myeloproliferative neoplasm-associated JAK2 V617F mutant.
Critical roles of Myc-ODC axis in the cellular transformation induced by myeloproliferative neoplasm-associated JAK2 V617F mutant.
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DOI：
10.1371/journal.pone.0052844
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tago K
中科院分区：
文献类型：
--
作者：
Funakoshi-Tago M;Sumi K;Kasahara T;Tago K
Janus kinase2(JAK2)的获得性突变(V617F)在大多数骨髓增生性肿瘤(MPN)患者中观察到。在JAK2(V617F)诱导表达基因的筛选中，我们发现STAT5的激活对c-Myc基因的表达有显著的诱导作用。有趣的是，在JAK2(V617F)转化的BA/F3细胞中，GSK-3β被灭活，从而增强了c-Myc的蛋白表达。C-Myc的表达增强促进了细胞的增殖，但不能抑制生长因子剥夺所致的细胞死亡；而抑制c-Myc的β表达则完全抑制了表达c-Myc的细胞的凋亡。值得注意的是，c-Myc T58A突变体以生长因子非依赖性的方式表现出更高的增殖活性，但该突变体未能诱导细胞凋亡。此外，c-Myc基因的敲除显著抑制了JAK2(V617F)转化细胞的增殖，提示c-Myc在JAK2(V617F)的致癌活性中起重要作用。此外，JAK2(V617F)还诱导了c-Myc的靶基因鸟氨酸脱羧酶(ODC)的表达，ODC是多胺生物合成中的限速酶。ODC抑制剂二氟甲基鸟氨酸(DFMO)可抑制JAK2(V617F)转化细胞的增殖。重要的是，DFMO有效地延缓了JAK2(V617F)转化细胞裸鼠移植瘤的形成，延长了裸鼠的存活时间；因此，通过c-Myc表达ODC是JAK2(V617F)诱导转化的关键步骤，DFMO可以作为MPN的有效治疗手段。
The acquired mutation (V617F) of Janus kinase 2 (JAK2) is observed in the majority of patients with myeloproliferative neoplasms (MPNs). In the screening of genes whose expression was induced by JAK2 (V617F), we found the significant induction of c-Myc mRNA expression mediated by STAT5 activation. Interestingly, GSK-3β was inactivated in transformed Ba/F3 cells by JAK2 (V617F), and this enhanced the protein expression of c-Myc. The enforced expression of c-Myc accelerated cell proliferation but failed to inhibit apoptotic cell death caused by growth factor deprivation; however, the inhibition of GSK-3β completely inhibited the apoptosis of cells expressing c-Myc. Strikingly, c-Myc T58A mutant exhibited higher proliferative activity in a growth-factor-independent manner; however, this mutant failed to induce apoptosis. In addition, knockdown of c-Myc significantly inhibited the proliferation of transformed cells by JAK2 (V617F), suggesting that c-Myc plays an important role in oncogenic activity of JAK2 (V617F). Furthermore, JAK2 (V617F) induced the expression of a target gene of c-Myc, ornithine decarboxylase (ODC), known as the rate-limiting enzyme in polyamine biosynthesis. An ODC inhibitor, difluoromethylornithine (DFMO), prevented the proliferation of transformed cells by JAK2 (V617F). Importantly, administration of DFMO effectively delayed tumor formation in nude mice inoculated with transformed cells by JAK2 (V617F), resulting in prolonged survival; therefore, ODC expression through c-Myc is a critical step for JAK2 (V617F)-induced transformation and DFMO could be used as effective therapy for MPNs.
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影响因子：
5.6
作者：
Abe, Miyuki;Funakoshi-Tago, Megumi;Kasahara, Tadashi
通讯作者：
Kasahara, Tadashi
DOI：
10.1016/j.bbrc.2009.04.015
发表时间：
2009-06-12
影响因子：
3.1
作者：
Furuhata, A.;Kimura, A.;Murate, T.
通讯作者：
Murate, T.
新型STAT5靶基因的体内鉴定。
影响因子：
14.9
作者：
Basham, Beth;Sathe, Manjiri;Grein, Jeffrey;McClanahan, Terrill;D'Andrea, Annalisa;Lees, Emma;Rascle, Anne
通讯作者：
Rascle, Anne
影响因子：
4.8
作者：
Funakoshi-Tago, Megumi;Tago, Kenji;Kasahara, Tadashi
通讯作者：
Kasahara, Tadashi
影响因子：
19
作者：
Bouchard, C;Staller, P;Eilers, M
通讯作者：
Eilers, M