Tristetraprolin induces cell cycle arrest in breast tumor cells through targeting AP-1/c-Jun and NF-κB pathway.
The main characteristic of cancers, including breast cancer, is the ability of cancer cells to proliferate uncontrollably. However, the underlying mechanisms of cancer cell proliferation, especially those regulated by the RNA binding protein tristetraprolin (TTP), are not completely understood. In this study, we found that TTP inhibits cell proliferation in vitro and suppresses tumor growth in vivo through inducing cell cycle arrest at the S phase. Our studies demonstrate that TTP inhibits c-Jun expression through the C-terminal Zn finger and therefore increases Wee1 expression, a regulatory molecule which controls cell cycle transition from the S to the G2 phase. In contrast to the well-known function of TTP in regulating mRNA stability, TTP inhibits c-Jun expression at the level of transcription by selectively blocking NF-κB p65 nuclear translocation. Reconstitution of NF-κB p65 completely abolishes the inhibition of c-Jun transcription by TTP. Moreover, reconstitution of c-Jun in TTP-expressing breast tumor cells diminishes Wee1 overexpression and promotes cell proliferation. Our results indicate that TTP suppresses c-Jun expression that results in Wee1 induction which causes cell cycle arrest at the S phase and inhibition of cell proliferation. Our study provides a new pathway for TTP function as a tumor suppressor which could be targeted in tumor treatment.
Department of Respiratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.|Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
Li
L
Xu
Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
Huan
H
Ning
Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
Ling
L
Gu
Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
Qinghong
Q
Wang
Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
Wenbao
W
Lu
Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
Hui
H
Peng
Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
Weiguang
W
Cui
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
Baoling
B
Ying
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
Christina R
CR
Ross
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
Gerald M
GM
Wilson
Department of Immunology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, China.
Lin
L
Wei
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
William S M
WS
Wold
Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
Jianguo
J
Liu
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; C498143:RELA protein, human; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human
AP-1; apoptosis; breast cancer; cell cycle; tristetraprolin