Kras promotes myeloid differentiation through Wnt/β‐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 differentiati...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-07-01
|
| Series: | FASEB BioAdvances |
| Subjects: | |
| Online Access: | https://doi.org/10.1096/fba.2019-00004 |
| _version_ | 1818267557876989952 |
|---|---|
| author | Noriko Yokoyama Yeon‐Jeong Kim Yoshio Hirabayashi Yoko Tabe Kenji Takamori Hideoki Ogawa Kazuhisa Iwabuchi |
| author_facet | Noriko Yokoyama Yeon‐Jeong Kim Yoshio Hirabayashi Yoko Tabe Kenji Takamori Hideoki Ogawa Kazuhisa Iwabuchi |
| author_sort | Noriko Yokoyama |
| collection | DOAJ |
| description | 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. 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. |
| first_indexed | 2024-12-12T20:24:30Z |
| format | Article |
| id | doaj.art-a5dea85e689d4771ac887ad82b915e25 |
| institution | Directory Open Access Journal |
| issn | 2573-9832 |
| language | English |
| last_indexed | 2024-12-12T20:24:30Z |
| publishDate | 2019-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj.art-a5dea85e689d4771ac887ad82b915e252022-12-22T00:13:12ZengWileyFASEB BioAdvances2573-98322019-07-011743544910.1096/fba.2019-00004Kras promotes myeloid differentiation through Wnt/β‐catenin signalingNoriko Yokoyama0Yeon‐Jeong Kim1Yoshio Hirabayashi2Yoko Tabe3Kenji Takamori4Hideoki Ogawa5Kazuhisa Iwabuchi6Institute for Environmental and Gender Specific Medicine Juntendo University Graduate School of Medicine Urayasu Chiba JapanLaboratory for Neuronal Growth Mechanisms Riken Brain Science Institutes Saitama JapanInstitute for Environmental and Gender Specific Medicine Juntendo University Graduate School of Medicine Urayasu Chiba JapanDepartment of Laboratory Medicine Juntendo University School of Medicine Hospital Hongo Tokyo JapanInstitute for Environmental and Gender Specific Medicine Juntendo University Graduate School of Medicine Urayasu Chiba JapanInstitute for Environmental and Gender Specific Medicine Juntendo University Graduate School of Medicine Urayasu Chiba JapanInstitute for Environmental and Gender Specific Medicine Juntendo University Graduate School of Medicine Urayasu Chiba JapanAbstract 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.https://doi.org/10.1096/fba.2019-00004GSK3βHL‐60 cell differentiationtumor suppressorwild‐type KrasWnt/β-catenin |
| spellingShingle | Noriko Yokoyama Yeon‐Jeong Kim Yoshio Hirabayashi Yoko Tabe Kenji Takamori Hideoki Ogawa Kazuhisa Iwabuchi Kras promotes myeloid differentiation through Wnt/β‐catenin signaling FASEB BioAdvances GSK3β HL‐60 cell differentiation tumor suppressor wild‐type Kras Wnt/β-catenin |
| title | Kras promotes myeloid differentiation through Wnt/β‐catenin signaling |
| title_full | Kras promotes myeloid differentiation through Wnt/β‐catenin signaling |
| title_fullStr | Kras promotes myeloid differentiation through Wnt/β‐catenin signaling |
| title_full_unstemmed | Kras promotes myeloid differentiation through Wnt/β‐catenin signaling |
| title_short | Kras promotes myeloid differentiation through Wnt/β‐catenin signaling |
| title_sort | kras promotes myeloid differentiation through wnt β catenin signaling |
| topic | GSK3β HL‐60 cell differentiation tumor suppressor wild‐type Kras Wnt/β-catenin |
| url | https://doi.org/10.1096/fba.2019-00004 |
| work_keys_str_mv | AT norikoyokoyama kraspromotesmyeloiddifferentiationthroughwntbcateninsignaling AT yeonjeongkim kraspromotesmyeloiddifferentiationthroughwntbcateninsignaling AT yoshiohirabayashi kraspromotesmyeloiddifferentiationthroughwntbcateninsignaling AT yokotabe kraspromotesmyeloiddifferentiationthroughwntbcateninsignaling AT kenjitakamori kraspromotesmyeloiddifferentiationthroughwntbcateninsignaling AT hideokiogawa kraspromotesmyeloiddifferentiationthroughwntbcateninsignaling AT kazuhisaiwabuchi kraspromotesmyeloiddifferentiationthroughwntbcateninsignaling |