%0 Journal Article
%T In Silico Inhibition Studies of Jun-Fos-DNA Complex Formation by Curcumin Derivatives
%A Anil Kumar
%A Utpal Bora
%J International Journal of Medicinal Chemistry
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/316972
%X Activator protein-1 (AP1) is a transcription factor that consists of the Jun and Fos family proteins. It regulates gene expression in response to a variety of stimuli and controls cellular processes including proliferation, transformation, inflammation, and innate immune responses. AP1 binds specifically to 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element 5¡ä-TGAG/CTCA-3¡ä (AP1 site). It has been found constitutively active in breast, ovarian, cervical, and lung cancers. Numerous studies have shown that inhibition of AP1 could be a promising strategy for cancer therapeutic applications. The present in silico study provides insights into the inhibition of Jun-Fos-DNA complex formation by curcumin derivatives. These derivatives interact with the amino acid residues like Arg155 and Arg158 which play a key role in binding of Jun-Fos complex to DNA (AP1 site). Ala151, Ala275, Leu283, and Ile286 were the residues present at binding site which could contribute to hydrophobic contacts with inhibitor molecules. Curcumin sulphate was predicted to be the most potent inhibitor amongst all the natural curcumin derivatives docked. 1. Introduction Activator protein-1 (AP1) is a transcription factor that consists of either homo- or heterodimers of the Jun and Fos family proteins [1]. It regulates gene expression in response to a variety of stimuli, including environmental stresses, UV radiation, cytokines, and growth factors. AP1 in turn controls a number of cellular processes including proliferation, transformation, inflammation, and innate immune response. The Jun and Fos proteins share similar amino acid sequences that comprise the basic DNA-binding sequence and the adjacent leucine zipper region by which these proteins dimerize [2¨C4]. The AP1 transcription factor binds specifically to 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element 5¡ä-TGAG/CTCA-3¡ä which is commonly referred to as the AP1 site [5, 6]. C-fos and c-jun genes are autoregulated; the transcription of c-jun is stimulated by its own product, and in contrast c-fos is negatively autoregulated [7¨C9]. AP1 has been found constitutively active in many cancers including breast, ovarian, cervical, and lung. Numerous studies have shown that inhibition of AP1 has a profound effect on the behavior of cancer cells and tumors suggesting that AP1 could be a promising target for cancer therapy [10]. Curcumin, a dietary spice derived from the plant Turmeric (Curcuma longa), is used as a traditional medicine for inflammatory conditions [11]. Further, curcumin has been reported to have
%U http://www.hindawi.com/journals/ijmc/2012/316972/