| First Author | Yao K | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 48 | Pages | 12791-12796 |
| PubMed ID | 29133416 | Mgi Jnum | J:253751 |
| Mgi Id | MGI:6102532 | Doi | 10.1073/pnas.1710756114 |
| Citation | Yao K, et al. (2017) RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth. Proc Natl Acad Sci U S A 114(48):12791-12796 |
| abstractText | Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNgamma secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNgamma decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNgamma in the RSK2 KO mice compared with the WT mice. Since IFNgamma is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate Ifngamma gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNgamma expression, because knockdown of RSK2 expression or overexpression of mutant T-bet reduces IFNgamma mRNA expression. To verify the function of the phosphorylation sites, we overexpressed a constitutively active mutant T-bet (S498E/S502E) in bone marrow. Mutant T-bet restored the IFNgamma mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for the inhibition of colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNgamma signaling. |
