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그림. HSP90 저해제인 17AAG 사용 시, Smads의 핵 내 이동 저해 효과​

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. 

Author information

Lee J1, An YS1, Kim MR1, Kim YA1, Lee JK2, Hwang CS3, Chung E4, Park IC5, Yi JY1.​

1Division of Radiation Effects, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.

2Radiation Blood Specimen Biobank, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.

3Human Resource Biobank, Cheil General Hospital, Catholic Kwandong University, College of Medicine, Seoul, Korea.

4Department of Genetic Engineering, College of Life Science, Kyung Hee University, Yongin, Gyeonggi-do, Korea.

5Division of Radiation Cancer Research, Korea Institute of Radiation and Medical Sciences, Seoul, Korea.