title: c-Jun N-terminal kinase/c-Jun inhibits fibroblast proliferation by negatively regulating the levels of stathmin/oncoprotein 18.
abstract: The JNKs (c-Jun N-terminal kinases) are stress-activated serine/threonine kinases that can regulate both cell death and cell proliferation. We have developed a cell system to control JNK re-expression at physiological levels in JNK1/2-null MEFs (murine embryonic fibroblasts). JNK re-expression restored basal and stress-activated phosphorylation of the c-Jun transcription factor and attenuated cellular proliferation with increased cells in G1/S-phase of the cell cycle. To explore JNK actions to regulate cell proliferation, we evaluated a role for the cytosolic protein, STMN (stathmin)/Op18 (oncoprotein 18). STMN, up-regulated in a range of cancer types, plays a crucial role in the control of cell division through its regulation of microtubule dynamics of the mitotic spindle. In JNK1/2-null or c-Jun-null MEFs or cells treated with c-Jun siRNA (small interfering RNA), STMN levels were significantly increased. Furthermore, a requirement for JNK/cJun signalling was demonstrated by expression of wild-type c-Jun, but not a phosphorylation-defective c-Jun mutant, being sufficient to down-regulate STMN. Critically, shRNA (small hairpin RNA)-directed STMN down-regulation in JNK1/2-null MEFs attenuated proliferation. Thus JNK/c-Jun regulation of STMN levels provides a novel pathway in regulation of cell proliferation with important implications for understanding the actions of JNK as a physiological regulator of the cell cycle and tumour suppressor protein.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC, Australia.
authors.forename: Yvonne Y C
authors.initials: YY
authors.lastname: Yeap
authors.forename: Ivan H W
authors.initials: IH
authors.lastname: Ng
authors.forename: Bahareh
authors.initials: B
authors.lastname: Badrian
authors.forename: Tuong-Vi
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Yan Y
authors.initials: YY
authors.lastname: Yip
authors.forename: Amardeep S
authors.initials: AS
authors.lastname: Dhillon
authors.forename: Steven E
authors.initials: SE
authors.lastname: Mutsaers
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Marie A
authors.initials: MA
authors.lastname: Bogoyevitch
authors.forename: Dominic C H
authors.initials: DC
authors.lastname: Ng
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D050777:Stathmin; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8