Critical role of FANCC in JAK2 V617F mutant-induced resistance to DNA cross-linking drugs

Fumihito Ueda, Kazuya Sumi, Kenji Tago, Tadashi Kasahara, Megumi Tago

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2115-2124
Number of pages10
JournalCellular Signalling
Volume25
Issue number11
DOIs
Publication statusPublished - 2013 Nov

Fingerprint

Janus Kinase 2
DNA
Pharmaceutical Preparations
Bleomycin
Mitomycin
DNA Damage
Fanconi Anemia Complementation Group Proteins
STAT5 Transcription Factor
Fanconi Anemia
Neoplasms
Point Mutation
Protein-Tyrosine Kinases
Cisplatin

Keywords

  • CDDP
  • FANCC
  • JAK2
  • MMC
  • Myeloproliferative neoplasm
  • V617F mutation

ASJC Scopus subject areas

  • Cell Biology

Cite this

Critical role of FANCC in JAK2 V617F mutant-induced resistance to DNA cross-linking drugs. / Ueda, Fumihito; Sumi, Kazuya; Tago, Kenji; Kasahara, Tadashi; Tago, Megumi.

In: Cellular Signalling, Vol. 25, No. 11, 11.2013, p. 2115-2124.

Research output: Contribution to journalArticle

Ueda, Fumihito ; Sumi, Kazuya ; Tago, Kenji ; Kasahara, Tadashi ; Tago, Megumi. / Critical role of FANCC in JAK2 V617F mutant-induced resistance to DNA cross-linking drugs. In: Cellular Signalling. 2013 ; Vol. 25, No. 11. pp. 2115-2124.
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