PMID- 29133416
OWN - NLM
STAT- MEDLINE
DCOM- 20180627
LR  - 20181113
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 114
IP  - 48
DP  - 2017 Nov 28
TI  - RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth.
PG  - 12791-12796
LID - 10.1073/pnas.1710756114 [doi]
AB  - 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.
FAU - Yao, Ke
AU  - Yao K
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
AD  - China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.
FAU - Peng, Cong
AU  - Peng C
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
AD  - Department of Dermatology, Xiangya Hospital, Central South University, Changsha
      410011, China.
FAU - Zhang, Yuwen
AU  - Zhang Y
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Zykova, Tatyana A
AU  - Zykova TA
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Lee, Mee-Hyun
AU  - Lee MH
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
AD  - China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.
FAU - Lee, Sung-Young
AU  - Lee SY
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Rao, Enyu
AU  - Rao E
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Chen, Hanyong
AU  - Chen H
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Ryu, Joohyun
AU  - Ryu J
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Wang, Lei
AU  - Wang L
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Zhang, Yi
AU  - Zhang Y
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
AD  - China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.
AD  - School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
FAU - Gao, Ge
AU  - Gao G
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
AD  - China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.
AD  - School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
FAU - He, Wei
AU  - He W
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
AD  - China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.
FAU - Ma, Wei-Ya
AU  - Ma WY
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Liu, Kangdong
AU  - Liu K
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
AD  - China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.
AD  - School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
FAU - Bode, Ann M
AU  - Bode AM
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912.
FAU - Dong, Ziming
AU  - Dong Z
AD  - School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
FAU - Li, Bing
AU  - Li B
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912;
      zgdong@hi.umn.edu b.li@louisville.edu.
FAU - Dong, Zigang
AU  - Dong Z
AD  - The Hormel Institute, University of Minnesota, Austin, MN 55912;
      zgdong@hi.umn.edu b.li@louisville.edu.
LA  - eng
GR  - R01 CA187027/CA/NCI NIH HHS/United States
GR  - R01 CA196639/CA/NCI NIH HHS/United States
GR  - R21 CA172457/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171113
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Isoenzymes)
RN  - 0 (T-Box Domain Proteins)
RN  - 0 (T-box transcription factor TBX21)
RN  - 452VLY9402 (Serine)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
SB  - IM
MH  - Animals
MH  - Bone Marrow Transplantation
MH  - Colonic Neoplasms/*genetics/immunology/pathology
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Interferon-gamma/*genetics/immunology
MH  - Isoenzymes/genetics/immunology
MH  - Leukocytes, Mononuclear/immunology/pathology
MH  - Liver Neoplasms/*genetics/immunology/prevention & control/secondary
MH  - Lung Neoplasms/*genetics/immunology/prevention & control/secondary
MH  - Male
MH  - Mice
MH  - Phosphorylation
MH  - Ribosomal Protein S6 Kinases/*genetics/immunology
MH  - Serine/metabolism
MH  - Signal Transduction
MH  - T-Box Domain Proteins/*genetics/immunology
MH  - Transfection
MH  - Whole-Body Irradiation
PMC - PMC5715759
OTO - NOTNLM
OT  - *IFN gamma
OT  - *RSK2
OT  - *T-bet
OT  - *growth
OT  - *metastasis
COIS- The authors declare no conflict of interest.
EDAT- 2017/11/15 06:00
MHDA- 2018/06/28 06:00
CRDT- 2017/11/15 06:00
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2018/06/28 06:00 [medline]
PHST- 2017/11/15 06:00 [entrez]
AID - 1710756114 [pii]
AID - 10.1073/pnas.1710756114 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12791-12796. doi:
      10.1073/pnas.1710756114. Epub 2017 Nov 13.