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Radicicol‐mediated inhibition of Bcr‐Ab1 in K562 cells induced p38‐MAPK dependent erythroid differentiation and PU.1 down‐regulation
Author(s) -
Morceau Franck,
Buck Isabelle,
Dicato Mario,
Diederich Marc
Publication year - 2008
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.5520340407
Subject(s) - k562 cells , chronic myelogenous leukemia , hsp90 , breakpoint cluster region , microbiology and biotechnology , transcription factor , biology , mapk/erk pathway , p38 mitogen activated protein kinases , imatinib , abl , tyrosine kinase , chemistry , cancer research , heat shock protein , kinase , leukemia , signal transduction , myeloid leukemia , gene , biochemistry , immunology
Constitutive tyrosine kinase activity of the breakpoint cluster region (Bcr)‐Abl fusion protein is characteristic of chronic myelogenous leukemia (CML). As resistance against Imatinib a Bcr‐abl inhibitor used in CML, was described, Heat shock protein (Hsp90) became an alternative target as inhibition of Bcr‐Abl‐Hsp90 complex leads to proliferation arrest. Here, we used natural product Radicicol (Rad), a macrocyclic antifungal, as an Hsp90 inhibitor to investigate the effect of Bcr‐Ab1 inactivation on erythroid gene expression and subsequently on the transcription factors involved in their regulation. We showed that all erythroid genes studied were over‐expressed after Rad treatment while Bcr‐Abl expression was inhibited. Specific transcription factor NF‐E2 was induced in Rad‐treated cells as well as GATA‐1 cofactors Friend of GATA (FOG)1 and SP1, whereas PU.1 was downregulated. Moreover, p38 mitogen activated protein kinase (MAPK) inhibition prevented Rad‐mediated differentiation of K562 in correlation with decreased γ‐globin expression and suppression of Rad‐mediated inhibition of PU.1. In conclusion, our results show that Radicicol leads to Bcr‐Abl inactivation via Hsp90 inhibition inducing reactivation of the erythroid program in K562 cells.