Critical role of FANCC in JAK2 V617F mutant-induced resistance to DNA cross-linking drugs.
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.
['Ueda|Fumihito|F|', 'Sumi|Kazuya|K|', 'Tago|Kenji|K|', 'Kasahara|Tadashi|T|', 'Funakoshi-Tago|Megumi|M|']
D000818:Animals D000970:Antineoplastic Agents D001402:B-Lymphocytes D001761:Bleomycin D045744:Cell Line, Tumor D002945:Cisplatin D004249:DNA Damage D004273:DNA, Neoplasm D019008:Drug Resistance, Neoplasm D052218:Fanconi Anemia Complementation Group C Protein D015972:Gene Expression Regulation, Neoplastic D053614:Janus Kinase 2 D051379:Mice D016685:Mitomycin D009154:Mutation D050799:STAT5 Transcription Factor D015398:Signal Transduction
FANCC JAK2 Janus kinase 2 Myeloproliferative neoplasm Myeloproliferative neoplasm MPNs CDDP MMC Fanconi anemia FA signal transducers and activators of transcription 5 STAT5 ATM ET Epo EpoR PMF PV RT-PCR TAE TBE Tris–acetic acid–EDTA Tris–boric acid–EDTA V617F mutation ataxia-telangiectasia mutated erythropoietin erythropoietin receptor essential thrombocythemia myeloproliferative neoplasms polycythemia vera primary myelofibrosis reverse transcriptase-polymerase chain reaction