Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma

被引:60
作者
Nakahata, S. [1 ]
Yamazaki, S. [2 ]
Nakauchi, H. [2 ]
Morishita, K. [1 ]
机构
[1] Miyazaki Univ, Fac Med, Dept Med Sci, Div Tumor & Cellular Biochem, Miyazaki 8891692, Japan
[2] Univ Tokyo, Inst Med Sci, Ctr Med Expt, Lab Stem Cell Therapy, Tokyo, Japan
基金
日本学术振兴会;
关键词
ZEB1; Smad7; ATLL; FACTOR-BETA; POTENTIAL MECHANISM; LEUKEMIA-CELLS; LEUKEMOGENESIS; EXPRESSION; RECEPTOR; GENE; TAX; COREPRESSOR; DEGRADATION;
D O I
10.1038/onc.2010.172
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Zinc-finger E-box binding homeobox 1 (ZEB1) is a candidate tumor-suppressor gene in adult T-cell leukemia/lymphoma ( ATLL). ZEB1 binds phosphorylated Smad2/3 to enhance transforming growth factor-beta 1 (TGF-beta 1) signaling. In addition to downregulation of ZEB1 mRNA, we found overexpression of inhibitory Smad, Smad7, in resistance of ATLL cells to growth suppression by TGF-beta 1. A protein complex of Smad7 and histone deacetylase constantly bound to the promoter region of TGF-beta 1 responsive genes with the Smad-responsive element (SRE) to inhibit TGF-beta 1 signaling; however, ectopic expression of ZEB1 reactivated TGF-beta 1 signaling by binding to Smad7 and recruiting the Smad3/p300 histone acetyltransferase complex to the promoter after TGF-beta 1 stimulation in ATLL. Conversely, because ZEB1 mRNA was detected in the late stages of T-cell development, we used CTLL2 cells with ZEB1 expression, a murine peripheral T-cell lymphoma, and found that a complex of Smad3, Smad7 and ZEB1 was bound to the SRE of the p21(CDKN1A) promoter after the induction of Smad7 by TGF-beta 1 treatment. Because the duration of TGF-beta 1-induced transcriptional activation of PAI-1 and p21 was shortened in shZEB1-expressing CTLL2 cells, ZEB1 may have a role in enhancing TGF-beta 1 signaling by binding not only to Smad3 but also to Smad7 in the nucleus. Altogether, these results suggest that both ZEB1 downregulation and Smad7 overexpression contribute to resistance to TGF-beta 1-mediated growth suppression in ATLL. Oncogene ( 2010) 29, 4157-4169; doi: 10.1038/onc.2010.172; published online 31 May 2010
引用
收藏
页码:4157 / 4169
页数:13
相关论文
共 31 条
[1]   Human T-cell lymphotropic virus oncoprotein Tax represses TGF-β1 signaling in human T cells via c-Jun activation:: a potential mechanism of HTLV-I leukemogenesis [J].
Arnulf, B ;
Villemain, A ;
Nicot, C ;
Mordelet, E ;
Charneau, P ;
Kersual, J ;
Zermati, Y ;
Mauviel, A ;
Bazarbachi, A ;
Hermine, O .
BLOOD, 2002, 100 (12) :4129-4138
[2]   Smad6 as a transcriptional corepressor [J].
Bai, ST ;
Shi, XM ;
Yang, XL ;
Cao, X .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (12) :8267-8270
[3]   Mechanisms of disease:: Role of transforming growth factor β in human disease. [J].
Blobe, GC ;
Schiemann, WP ;
Lodish, HF .
NEW ENGLAND JOURNAL OF MEDICINE, 2000, 342 (18) :1350-1358
[4]   TGF-β signaling in tumor suppression and cancer progression [J].
Derynck, R ;
Akhurst, RJ ;
Balmain, A .
NATURE GENETICS, 2001, 29 (02) :117-129
[5]   Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation [J].
Ebisawa, T ;
Fukuchi, M ;
Murakami, G ;
Chiba, T ;
Tanaka, K ;
Imamura, T ;
Miyazono, K .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (16) :12477-12480
[6]   LONG-TERM CULTURE OF TUMOR-SPECIFIC CYTOTOXIC T-CELLS [J].
GILLIS, S ;
SMITH, KA .
NATURE, 1977, 268 (5616) :154-156
[7]   Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor [J].
Hata, A ;
Lagna, G ;
Massagué, J ;
Hemmati-Brivanlou, A .
GENES & DEVELOPMENT, 1998, 12 (02) :186-197
[8]   Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma [J].
Hidaka, Tomonori ;
Nakahata, Shingo ;
Hatakeyama, Kinta ;
Hamasaki, Makoto ;
Yamashita, Kiyoshi ;
Kohno, Takashi ;
Arai, Yasuhito ;
Taki, Tomohiko ;
Nishida, Kazuhiro ;
Okayama, Akihiko ;
Asada, Yujiro ;
Yamaguchi, Ryoji ;
Tsubouchi, Hirohito ;
Yokota, Jun ;
Taniwaki, Masafumi ;
Higashi, Yujiro ;
Morishita, Kazuhiro .
BLOOD, 2008, 112 (02) :383-393
[9]  
INGE TH, 1992, J IMMUNOL, V148, P3847
[10]   Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation [J].
Kavsak, P ;
Rasmussen, RK ;
Causing, CG ;
Bonni, S ;
Zhu, HT ;
Thomsen, GH ;
Wrana, JL .
MOLECULAR CELL, 2000, 6 (06) :1365-1375