Open AccessKras promotes myeloid differentiation through Wnt/β‐catenin signaling
Author(s) -
Yokoyama Noriko,
Kim YeonJeong,
Hirabayashi Yoshio,
Tabe Yoko,
Takamori Kenji,
Ogawa Hideoki,
Iwabuchi Kazuhisa
Publication year - 2019
Publication title -
faseb bioadvances
Language(s) - English
Resource type - Journals
ISSN - 2573-9832
DOI - 10.1096/fba.2019-00004
Subject(s) - kras , wnt signaling pathway , myeloid , cancer research , myeloid leukemia , signal transduction , cellular differentiation , chemistry , microbiology and biotechnology , phosphorylation , biology , biochemistry , mutation , gene
Wild‐type Kras, a small GTPase, inactivates Ras growth‐promoting signaling. However, the role of Kras in differentiation of myeloid cells remains unclear. This study showed the involvement of Kras in a novel regulatory mechanism underlying the dimethyl sulfoxide (DMSO)‐induced differentiation of human acute myeloid leukemia HL‐60 cells. Kras was found to positively regulate DMSO‐induced differentiation, with the activity of Kras increasing upon DMSO. Inhibition of Kras attenuated CD11b expression in differentiated HL‐60 cells. GSK3β, an important component of Wnt signaling, was found to be a downstream signal of Kras. Phosphorylation of GSK3β was markedly enhanced by DMSO treatment. Moreover, inhibition of GSK3β enhanced CD11b expression and triggered the accumulation in the nucleus of β‐catenin and Tcf in response to DMSO. Inhibitors of β‐catenin‐mediated pathways blocked CD11b expression, further indicating that β‐catenin is involved in the differentiation of HL‐60 cells. Elevated expression of C/EBPα and C/EBPɛ accompanied by the expression of granulocyte colony‐stimulating factor (G‐CSF) receptor was observed during differentiation. Taken together, these findings suggest that Kras engages in cross talk with the Wnt/β‐catenin pathway upon DMSO treatment of HL‐60 cells, thereby regulating the granulocytic differentiation of HL‐60 cells. These results indicate that Kras acts as a tumor suppressor during the differentiation of myeloid cells.