title: Heat Shock Protein 90 Regulates Subcellular Localization of Smads in Mv1Lu Cells.
abstract: Heat shock protein 90 (HSP90) regulates the stability of various proteins and plays an essential role in cellular homeostasis. Many client proteins of HSP90 are involved in cell growth, survival, and migration; processes that are generally accepted as participants in tumorigenesis. HSP90 is also up-regulated in certain tumors. Indeed, the inhibition of HSP90 is known to be effective in cancer treatment. Recently, studies showed that HSP90 regulates transforming growth factor β1 (TGF-β1)-induced transcription by increasing the stability of the TGF-β receptor. TGF-β signaling also has been implicated in cancer, suggesting the possibility that TGF-β1 and HSP90 function cooperatively during the cancer cell progression. Here in this paper, we investigated the role of HSP90 in TGF-β1-stimulated Mv1Lu cells. Treatment of Mv1Lu cells with the HSP90 inhibitor, 17-allylamino-demethoxy-geldanamycin (17AAG), or transfection with truncated HSP90 (ΔHSP90) significantly reduced TGF-β1-induced cell migration. Pretreatment with 17AAG or transfection with ΔHSP90 also reduced the levels of phosphorylated Smad2 and Smad3. In addition, the HSP90 inhibition interfered the nuclear localization of Smads induced by constitutively active Smad2 (S2EE) or Smad3 (S3EE). We also found that the HSP90 inhibition decreased the protein level of importin-β1 which is known to regulate R-Smad nuclear translocation. These data clearly demonstrate a novel function of HSP90; HSP90 modulates TGF-β signaling by regulating Smads localization. Overall, our data could provide a detailed mechanism linking HSP90 and TGF-β signaling. The extension of our understanding of HSP90 would offer a better strategy for treating cancer.
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.
authors.forename: Jeeyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.
authors.forename: You Sun
authors.initials: YS
authors.lastname: An
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.
authors.forename: Mi-Ra
authors.initials: MR
authors.lastname: Kim
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.
authors.forename: Ye-Ah
authors.initials: YA
authors.lastname: Kim
authors.affiliation: Radiation Blood Specimen Biobank, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Human Resource Biobank, Cheil General Hospital, Catholic Kwandong University, College of Medicine, Seoul, Korea.
authors.forename: Chang Sun
authors.initials: CS
authors.lastname: Hwang
authors.affiliation: Department of Genetic Engineering, College of Life Science, Kyung Hee University, Yongin, Gyeonggi-do, Korea.
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Chung
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Yi
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C112765:tanespimycin
keywords: 17AAG (17-ALLYLAMINO-DEMETHOXY-GELDANAMYCIN); HSP90 (HEAT SHOCK PROTEIN 90); SMADS; SUBCELLULAR LOCALIZATION; TGF-β1 (TRANSFORMING GROWTH FACTOR β1)