C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice.
More...C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression.
This SuperSeries is composed of the SubSeries listed below.
Overall design: Refer to individual Series
Less...| Accession | PRJNA281223; GEO: GSE67922 |
| Type | Umbrella project |
| Publications | Nakatsumi H et al., "Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages.", Cell Rep, 2017 Nov 28;21(9):2471-2486 |
| Submission | Registration date: 15-Apr-2015
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University |
| Relevance | Superseries |
Project Data:
| Resource Name | Number
of Links |
|---|
| Publications |
| PubMed | 1 |
| Other datasets |
| GEO DataSets | 3 |
GEO Data Details| Parameter | Value |
|---|
| Data volume, Spots | 466158 |
| Data volume, Processed Mbytes | 9 |
| Data volume, Supplementary Mbytes | 64 |
Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages encompasses the following 2 sub-projects:
| Project Type | Number of Projects |
| Transcriptome or Gene expression | 2 |
BioProject
accession | Organism | Title |
|---|
| PRJNA280975 | Homo sapiens | Gene expression alterations by the mTORC1-FOXK1 pathway (Department of Molecular and...) | | PRJNA280973 | Homo sapiens | Profiling gene expression of HeLa cells transfected with FOXK1 (Department of Molecular and...) |
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