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Kras promotes myeloid differentiation through Wnt/?-catenin signaling.

ABSTRACT: 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. GSK3?, an important component of Wnt signaling, was found to be a downstream signal of Kras. Phosphorylation of GSK3? was markedly enhanced by DMSO treatment. Moreover, inhibition of GSK3? enhanced CD11b expression and triggered the accumulation in the nucleus of ?-catenin and Tcf in response to DMSO. Inhibitors of ?-catenin-mediated pathways blocked CD11b expression, further indicating that ?-catenin is involved in the differentiation of HL-60 cells. Elevated expression of C/EBP? and C/EBP? 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/?-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.

SUBMITTER: Yokoyama N

PROVIDER: S-EPMC6996383 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Kras promotes myeloid differentiation through Wnt/β-catenin signaling.

Yokoyama Noriko N Kim Yeon-Jeong YJ Hirabayashi Yoshio Y Tabe Yoko Y Takamori Kenji K Ogawa Hideoki H Iwabuchi Kazuhisa K

FASEB bioAdvances 20190701 7

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 expressio ...[more]

PMID: 32123842

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Project description:Aberrant regulation of the Wnt/β-catenin signaling pathway is one of the major causes of colorectal cancer (CRC). Loss-of-function mutations in APC are commonly found in CRC, leading to inappropriate activation of canonical Wnt signaling. Conversely, gain-of-function mutations in KRAS and BRAF genes are detected in up to 60% of CRCs. Whereas KRAS/mitogen-activated protein kinase (MAPK) and canonical Wnt/β-catenin pathways are critical for intestinal tumorigenesis, mechanisms integrating these two important signaling pathways during CRC development are unknown. Results herein demonstrate that transformation of normal intestinal epithelial cells (IECs) by oncogenic forms of KRAS, BRAF or MEK1 was associated with a marked increase in β-catenin/TCF4 and c-MYC promoter transcriptional activities and mRNA levels of c-Myc, Axin2 and Lef1. Notably, expression of a dominant-negative mutant of T-Cell Factor 4 (ΔNTCF4) severely attenuated IEC transformation induced by oncogenic MEK1 and markedly reduced their tumorigenic and metastatic potential in immunocompromised mice. Interestingly, the Frizzled co-receptor LRP6 was phosphorylated in a MEK-dependent manner in transformed IECs and in human CRC cell lines. Expression of LRP6 mutant in which serine/threonine residues in each particular ProlineProlineProlineSerine/ThreonineProline motif were mutated to alanines (LRP6-5A) significantly reduced β-catenin/TCF4 transcriptional activity. Accordingly, MEK inhibition in human CRC cells significantly diminished β-catenin/TCF4 transcriptional activity and c-MYC mRNA and protein levels without affecting β-catenin expression or stability. Lastly, LRP6 phosphorylation was also increased in human colorectal tumors, including adenomas, in comparison with healthy adjacent normal tissues. Our data indicate that oncogenic activation of KRAS/BRAF/MEK signaling stimulates the canonical Wnt/β-catenin pathway, which in turn promotes intestinal tumor growth and invasion. Moreover, LRP6 phosphorylation by ERK1/2 may provide a unique point of convergence between KRAS/MAPK and Wnt/β-catenin signalings during oncogenesis.

Dataset Information

Kras promotes myeloid differentiation through Wnt/?-catenin signaling.

Publications

Kras promotes myeloid differentiation through Wnt/β-catenin signaling.

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