Abstract
We previously found that the adamantyl-substituted retinoid-related molecules bind to the small heterodimer partner (SHP) as well as the Sin3A complex. In this report, we delineated the role of SHP and the Sin3A complex in 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated inhibition of cell growth and apoptosis. We examined the effect of loss of SHP and Sin3A expression in a number of cell types on 3-Cl-AHPC-mediated growth inhibition and apoptosis induction, 3-Cl-AHPC-mediated nuclear factor-kappaB (NF-kappaB) activation, and 3-Cl-AHPC-mediated increase in c-Fos and c-Jun expression. We found that loss of SHP or Sin3A expression, while blocking 3-Cl-AHPC-mediated apoptosis, had little effect on 3-Cl-AHPC inhibition of cellular proliferation. We have previously shown that 3-Cl-AHPC-mediated NF-kappaB activation is necessary for apoptosis induction. We have now shown that 3-Cl-AHPC-enhanced c-Fos and c-Jun expression is also essential for maximal 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC induction of c-Fos and c-Jun expression as well as NF-kappaB activation was dependent on SHP protein levels. In turn, SHP levels are regulated by Sin3A because ablation of Sin3A resulted in a decrease in SHP expression. Thus, SHP and Sin3A play an important role in adamantyl-substituted retinoid-related induction of cellular apoptosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adamantane / analogs & derivatives*
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Adamantane / pharmacology
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Animals
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Apoptosis / drug effects*
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Blotting, Western
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Cell Line
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromatin Immunoprecipitation
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Cinnamates / pharmacology*
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Dose-Response Relationship, Drug
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Gene Expression / drug effects
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Histone Deacetylases / metabolism
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Humans
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NF-kappa B / metabolism*
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Protein Binding
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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RNA, Small Interfering / genetics
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Sin3 Histone Deacetylase and Corepressor Complex
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Transfection
Substances
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4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid
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Cinnamates
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NF-kappa B
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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RNA, Small Interfering
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Receptors, Cytoplasmic and Nuclear
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Repressor Proteins
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SIN3A transcription factor
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nuclear receptor subfamily 0, group B, member 2
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Histone Deacetylases
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Sin3 Histone Deacetylase and Corepressor Complex
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Adamantane