期刊
CANCER RESEARCH
卷 67, 期 1, 页码 318-325出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-2164
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资金
- NCI NIH HHS [P01 CA051993-080001, P01 CA051993-06A10001, P01 CA051993-09S10001, P01 CA051993-090001, P01 CA051993-070001, P01 CA051993-08S10001] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P01CA051993] Funding Source: NIH RePORTER
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.
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