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.
Highlights
Apoptosis has been associated with the induction as well as the repression of gene expression
We found that exposure of cells to adamantyl retinoid–related (ARR) resulted in the enhanced association of small heterodimer partner (SHP) with the Sin3A complex and modification of the Sin3A complex with the enhanced binding of N-CoR, histone deacetylases (HDAC)-4, and HSP90 and increased Sin3A-associated HDAC activity
We assessed whether SHP and or Sin3A expression were essential for ARR-mediated growth inhibition as well as induction of apoptosis, ARR binding to nuclear extracts, and ARR modulation of Sin3A-associated HDAC activity in a number of cell types
Summary
Apoptosis has been associated with the induction as well as the repression of gene expression. HDACs are often found associated with large multimolecular repressor complexes such as the Sin3A, the NURD/NED/M12, and the CoREST complexes [1] These are often targeted to specific DNA sequences by the binding of nuclear transcription factors. Sin3A and Sin3B contain four highly conserved paired amphipathic helix domains through which the Sin complexes bind specific nuclear transcription factors [2, 5,6,7] These include the MAD family members p53, E2F-4, p33ING1, MNFβ, Ikaros, MeCP2, and ELK1 as well as the mortality factors MORF4, MRGX, and MRG15 [2]. The event(s) that triggers the binding of these nuclear transcription factors to the Sin3A complex and targets the repressor complex to the transcription factor consensus sequences, resulting in subsequent repression of gene transcription rather than its induction, has not been delineated. Once bound to DNA, the Sin3A complex can modify the histone structure through the presence of a number of proteins that are part of the complex, including Swi/Snf chromatin remodeling complex subunits, O-linked N-acetylglucosamine transferases, and histone methyltransferases [8,9,10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
