Critical role of FANCC in JAK2 V617F mutant-induced resistance to DNA cross-linking drugs.
Critical role of FANCC in JAK2 V617F mutant-induced resistance to DNA cross-linking drugs.
复制标题
FANCC 在 JAK2 V617F 突变体诱导的 DNA 交联药物耐药性中发挥关键作用。
DOI：
10.1016/j.cellsig.2013.07.003
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发表时间：
2013
期刊：
影响因子：
4.8
通讯作者：
Funakoshi-Tago M
中科院分区：
文献类型：
--
作者：
Ueda F;Sumi K;Tago K;Kasahara T;Funakoshi-Tago M
酪氨酸激酶Janus激酶2（JAK2）的点突变（V617 F）在大多数骨髓增生性肿瘤（MPN）患者中被发现，并且由组成性活性JAK2 V617 F突变体诱导的异常信号传导通路是MPN的标志。JAK2 V617F突变体转化的细胞对顺铂（CDDP）、丝裂霉素C（MMC）和博来霉素（BLM）等抗癌药物表现出耐药性。我们首次发现JAK2 V617F突变体通过激活信号转导和转录激活因子5（STAT5）显著诱导Fanconi贫血（FA）蛋白FANCC的表达。此外，与表达野生型JAK 2的细胞相比，在JAK 2 V617 F突变体转化的细胞中，FANCD 2的单偶联和病灶形成增加，这对于FA途径的激活至关重要。有趣的是，在表达JAK 2 V617 F突变体的细胞中敲低FANCC不仅诱导FANCD 2的单偶联和灶形成减少，而且还增强了对CDDP和MMC诱导的DNA损伤的敏感性，而不是BLM。综上所述，FANCC最有可能是JAK2 V617 F突变体转化的细胞对DNA交联药物诱导的DNA损伤的抗性的关键。
A point mutation (V617F) of tyrosine kinase Janus kinase 2 (JAK2) is found in the majority of patients with myeloproliferative neoplasms (MPNs) and an aberrant signaling pathway induced by constitutively active JAK2 V617F mutant is a hallmark of MPNs. Cells transformed by JAK2 V617F mutant exhibited resistance to anti-cancer drugs such as cisplatin (CDDP), mitomycin C (MMC) and bleomycin (BLM). We first found that the expression of FANCC, a member of the Fanconi anemia (FA) proteins, was significantly induced by JAK2 V617F mutant through activation of signal transducers and activators of transcription 5 (STAT5). In addition, monoubiqitination and foci formation of FANCD2, which are critical for activation of the FA pathway, were increased in cells transformed by JAK2 V617F mutant, compared to cells expressing wild-type JAK2. Interestingly, knockdown of FANCC in cells expressing JAK2 V617F mutant induced not only the reduction of monoubiqitination and foci formation of FANCD2 but also the enhancement of sensitivity to DNA damage induced by CDDP and MMC but not BLM. Taken together, FANCC is most likely to be critical for resistance to DNA cross-linking drug-induced DNA damage in cells transformed by JAK2 V617F mutant.