title: Critical role of FANCC in JAK2 V617F mutant-induced resistance to DNA cross-linking drugs.
abstract: 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.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Tokyo 105-8512, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Ueda
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sumi
authors.forename: Kenji
authors.initials: K
authors.lastname: Tago
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001761:Bleomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D050799:STAT5 Transcription Factor; D001761:Bleomycin; D016685:Mitomycin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D002945:Cisplatin
keywords: ATM; CDDP; ET; Epo; EpoR; FA; FANCC; Fanconi anemia; JAK2; Janus kinase 2; MMC; MPNs; Myeloproliferative neoplasm; PMF; PV; RT-PCR; STAT5; 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; signal transducers and activators of transcription 5