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

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 with 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.
Mesh Terms:
Adamantane, Adenosine Triphosphatases, Apoptosis, Cell Line, Tumor, Cinnamates, HSP90 Heat-Shock Proteins, Histone Deacetylases, Humans, Naphthalenes, Protein Binding, Proto-Oncogene Proteins c-myc, Receptors, Cytoplasmic and Nuclear, Repressor Proteins
Cancer Res.
Date: Jan. 01, 2007
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