title: Transforming growth factor-β-stimulated clone-22 is a negative-feedback regulator of Ras / Raf signaling: Implications for tumorigenesis.
abstract: Transforming growth factor-β (TGF-β)-stimulated clone-22 (TSC-22), also called TSC22D1-2, is a putative tumor suppressor. We previously identified TSC-22 downstream of an active mutant of fms-like tyrosine kinase-3 (Flt3). Here, we show that TSC-22 works as a tumor suppressor through inhibiting Ras/Raf signaling. Notably, TSC-22 was upregulated by Ras/Raf activation, whereas its upregulation was inhibited by concurrent STAT5 activation. Although TSC-22 was normally retained in the cytoplasm by its nuclear export signal (NES), Ras/Raf activation caused nuclear translocation of TSC-22, but not TSC22D1-1. Unlike glucocorticoid-induced leucine zipper (GILZ/TSC22D3-2) previously characterized as a negative regulator of Ras/Raf signaling, TSC-22 failed to interact physically with Ras/Raf. Importantly, transduction with TSC-22, but not TSC22D1-1, suppressed the growth, transformation and tumorigenesis of NIH3T3 cells expressing oncogenic H-Ras: this suppression was enhanced by transduction with a TSC-22 mutant lacking NES that had accumulated in the nucleus. Collectively, upregulation and nuclear translocation of TSC-22 played an important role in the feedback suppression of Ras/Raf signaling. Consistently, TSC22D1-deficient mice were susceptible to tumorigenesis in a mouse model of chemically-induced liver tumors bearing active mutations of Ras/Raf. Thus, TSC-22 negatively regulated Ras/Raf signaling through a mechanism different from GILZ, implicating TSC-22 as a novel suppressor of oncogenic Ras/Raf-induced tumors.
authors.affiliation: Division of Cellular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Enomoto
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Koutarou
authors.initials: K
authors.lastname: Nishimura
authors.forename: Masamichi
authors.initials: M
authors.lastname: Isobe
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Komeno
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakahara
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Oki
authors.forename: Haruki
authors.initials: H
authors.lastname: Kume
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D004052:Diethylnitrosamine / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic; D047468:Immunoprecipitation; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D054448:Precursor Cells, B-Lymphoid; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C498608:Dsip1 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C490983:Tgfb1i4 protein, mouse; D014157:Transcription Factors; D004052:Diethylnitrosamine; D048490:raf Kinases; D018631:ras Proteins