Adamantyl-substituted retinoid-related molecules bind small heterodimer partner and modulate the Sin3A repressor

被引:67
作者
Farhana, Lulu
Dawson, Marcia I.
Leid, Mark
Wang, Li
Moore, David D.
Liu, Gang
Xia, Zeben
Fontana, Joseph A.
机构
[1] Wayne State Univ, Dingell Vet Affairs Med Ctr, Detroit, MI 48201 USA
[2] Wayne State Univ, Dept Med, Detroit, MI 48201 USA
[3] Karmanos Canc Inst, Detroit, MI USA
[4] Burnham Inst, La Jolla, CA 92037 USA
[5] Oregon State Univ, Coll Pharm, Dept Pharmaceut Sci, Corvallis, OR 97331 USA
[6] Univ Kansas, Med Ctr, Dept Med & Pharmacol, Kansas City, KS 66103 USA
[7] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
关键词
D O I
10.1158/0008-5472.CAN-06-2164
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) and 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) are inducers of apoptosis of malignant cells both in vitro and in vivo. Numerous mechanisms have been proposed for how these compounds exert this effect. This report shows that AHPN/ 3-Cl-AHPC binds specifically to the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), and this binding promotes interaction of the receptor wit 1 a corepressor complex that minimally contains Sin3A, N-CoR, histone deacetylase 4, and HSP90. Formation of the SHP-Sin3A complex is essential for the ability of AHPN and 3-Cl-AHPC to induce apoptosis, as both knockout SHP and knockdown of Sin3A compromise the proapoptotic activity of these compounds but not other apoptosis inducers. These results suggest that AHPN/3-Cl-AHPC and their analogues are SHP ligands and their induction of apoptosis is mediated by their binding to the SHP receptor.
引用
收藏
页码:318 / 325
页数:8
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