Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Tokyo 105-8512, Japan.
Cell Signal. 2013 Nov;25(11):2115-24. doi: 10.1016/j.cellsig.2013.07.003. Epub 2013 Jul 6.
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.
JAK2 激酶的点突变（V617F）存在于大多数骨髓增殖性肿瘤（MPN）患者中，由组成性激活的 JAK2 V617F 突变引起的异常信号通路是 MPN 的标志。由 JAK2 V617F 突变转化的细胞对顺铂（CDDP）、丝裂霉素 C（MMC）和博来霉素（BLM）等抗癌药物表现出耐药性。我们首先发现，信号转导子和转录激活子 5（STAT5）的激活显著诱导了 FANCC 的表达，FANCC 是范可尼贫血（FA）蛋白家族的成员。此外，与表达野生型 JAK2 的细胞相比，由 JAK2 V617F 突变转化的细胞中 FANCD2 的单泛素化和焦点形成增加，这对于 FA 途径的激活至关重要。有趣的是，在表达 JAK2 V617F 突变的细胞中敲低 FANCC 不仅诱导 FANCD2 的单泛素化和焦点形成减少，而且还增强了对 CDDP 和 MMC 诱导的 DNA 损伤的敏感性，但对 BLM 没有影响。综上所述，FANCC 很可能是 JAK2 V617F 突变转化的细胞对 DNA 交联药物诱导的 DNA 损伤耐药性的关键。
