TY - JOUR
T1 - Analysis of the mechanism of polycythemia vera by studying JAK2 mutant-induced signaling pathway
AU - Funakoshi-Tago, Megumi
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2011
Y1 - 2011
N2 - It has been well established that disruption of JAK2 signaling regulation is involved in various hematopoietic disorders; however, the detailed mechanism by which abnormal activation of JAK2 exhibits transforming activity remains to be elucidated. The somatic JAK2 mutation (V617F) was identified in most patients withpolycythemia vera (PV). Here, we show that JAK2 V617F mutant was constitutively active and exhibited tumorigenesis activity as a potent oncogene when erythropoietin receptor (EpoR) was co-expressed. To clarify the signaling pathway of JAK2 V617F mutant, we investigated the functional role of downstream transcription factor STAT5 in its induced cellular transformation and tumorigenesis in nude mice. Interestingly, JAK2 V617F mutant failed to exhibit transforming activity when STAT5 activation was inhibited utilizing EpoR mutant (HM). Furthermore, the expression of constitutively active STAT5 mutant (1*6) exhibited transforming activity. Taking these observations together, it is concluded STAT5 plays an essential role in EpoR-JAK2 V617F mutant-induced hematopoietic disorder and would be a good target for the treatment of PV.
AB - It has been well established that disruption of JAK2 signaling regulation is involved in various hematopoietic disorders; however, the detailed mechanism by which abnormal activation of JAK2 exhibits transforming activity remains to be elucidated. The somatic JAK2 mutation (V617F) was identified in most patients withpolycythemia vera (PV). Here, we show that JAK2 V617F mutant was constitutively active and exhibited tumorigenesis activity as a potent oncogene when erythropoietin receptor (EpoR) was co-expressed. To clarify the signaling pathway of JAK2 V617F mutant, we investigated the functional role of downstream transcription factor STAT5 in its induced cellular transformation and tumorigenesis in nude mice. Interestingly, JAK2 V617F mutant failed to exhibit transforming activity when STAT5 activation was inhibited utilizing EpoR mutant (HM). Furthermore, the expression of constitutively active STAT5 mutant (1*6) exhibited transforming activity. Taking these observations together, it is concluded STAT5 plays an essential role in EpoR-JAK2 V617F mutant-induced hematopoietic disorder and would be a good target for the treatment of PV.
KW - Janus kinase 2 (JAK2)
KW - Polycythemia vera
KW - STAT5
KW - V617F mutation
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U2 - 10.1248/yakushi.131.1183
DO - 10.1248/yakushi.131.1183
M3 - Review article
C2 - 21804321
AN - SCOPUS:79961038712
VL - 131
SP - 1183
EP - 1187
JO - Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
JF - Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
SN - 0031-6903
IS - 8
ER -