Dataset Information

Noncanonical pathway for regulation of CCL2 expression by an mTORC1-FOXK1 axis promotes recruitment of tumor-associated macrophages

ABSTRACT: 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. Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that is activated in various tumor cell types. We have now identified a noncanonical pathway for regulation of CCL2 production that is mediated by mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1, with dephosphorylation of FOXK1 in response to mTORC1 activation 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. Specific inhibition of FOXK1 may thus be a potential therapeutic strategy for cancer.

OTHER RELATED OMICS DATASETS IN: PRJNA280975PRJNA280973GSE67922PRJNA281223

INSTRUMENT(S): QSTAR

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Hirokazu Nakatsumi

LAB HEAD: Keiichi I. Nakayama

PROVIDER: PXD007996 | Pride | 2017-11-30

REPOSITORIES: Pride

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Publications

Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages.

Nakatsumi Hirokazu H Matsumoto Masaki M Nakayama Keiichi I KI

Cell reports 20171101 9

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 t ...[more]

PMID: 29186685

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Project description:Long non-coding RNAs (lncRNAs) are transcripts of more than 200 nucleotides that are not translated into functional proteins. Cellular lncRNAs have been shown to act as regulators by interacting with target nucleic acids or proteins and modulating their activities. We investigated the role of RNA1.2, which is one of four major lncRNAs expressed by human cytomegalovirus (HCMV), by comparing the properties of parental virus in vitro with those of deletion mutants lacking either most of the RNA1.2 gene or only the TATA element of the promoter. In comparison with parental virus, these mutants exhibited no growth defects and minimal differences in viral gene expression in human fibroblasts. In contrast, 76 cellular genes were consistently up- or down-regulated by the mutants at both the RNA and protein levels at 72 hours after infection. Differential expression of the gene most highly upregulated by the mutants (Tumor protein p63-regulated gene 1-like protein; TPRG1L) was confirmed at both levels by RT-PCR and immunoblotting. Consistent with the known ability of TPRG1L to upregulate IL-6 expression via NF-κB stimulation, RNA1.2 mutant-infected fibroblasts were observed to upregulate IL-6 in addition to TPRG1L. Comparable surface expression of TNF receptors and responsiveness to TNF-α in cells infected by the parental and mutant viruses indicated that activation of signaling by TNF-α is not involved in upregulation of IL-6 by the mutants. In contrast, inhibition of NF-κB activity and knockdown of TPRG1L expression reduced the extracellular release of IL-6 by RNA1.2 mutant-infected cells, thus demonstrating that upregulation of TPRG1L activates NF-κB. The levels of CCL2 and CXCL1 transcripts were also increased in RNA1.2 mutant-infected cells, further demonstrating the presence of active NF-κB signalling. These results suggest that RNA1.2 plays a role in manipulating intrinsic NF-B-dependent cytokine and chemokine release during HCMV infection , thereby impacting downstream immune responses.

Dataset Information

Noncanonical pathway for regulation of CCL2 expression by an mTORC1-FOXK1 axis promotes recruitment of tumor-associated macrophages

Publications

Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages.

Similar Datasets

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