Selective antagonism of cJun for cancer therapy
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(2020) 39:184
REVIEW
Open Access
Selective antagonism of cJun for cancer therapy Andrew Brennan1, James T. Leech2, Neil M. Kad2 and Jody M. Mason1*
Abstract The activator protein-1 (AP-1) family of transcription factors modulate a diverse range of cellular signalling pathways into outputs which can be oncogenic or anti-oncogenic. The transcription of relevant genes is controlled by the cellular context, and in particular by the dimeric composition of AP-1. Here, we describe the evidence linking cJun in particular to a range of cancers. This includes correlative studies of protein levels in patient tumour samples and mechanistic understanding of the role of cJun in cancer cell models. This develops an understanding of cJun as a focal point of cancer-altered signalling which has the potential for therapeutic antagonism. Significant work has produced a range of small molecules and peptides which have been summarised here and categorised according to the binding surface they target within the cJun-DNA complex. We highlight the importance of selectively targeting a single AP-1 family member to antagonise known oncogenic function and avoid antagonism of antioncogenic function. Keywords: c-Jun, Activator Protein-1, transcriptional regulator, basic leucine zipper, cancer, peptides, protein-protein interaction
Background Activator protein-1 (AP-1) designates a family of oncogenic transcription factors (TFs) that are integral components located at the end of a number of key signalling networks, controlling vital cellular processes such as differentiation, migration, proliferation and apoptosis [1– 6]. AP-1 functions as homo- or hetero-dimeric combinations of proteins in the Fos and Jun sub-families (a broader definition of AP-1 includes ATF and MAF subfamilies) [7, 8]. As a dimer, AP-1 binds to cognate DNA sites within gene promotor elements to influence the expression of a range of target genes that include cyclin D1, FasL, SDF1, TNFα, proliferin and CD44 [9–11]. This review will focus on cJun, an AP-1 family member which is found to be upregulated or overexpressed in a large number of cancers (for a list of cancers associated with * Correspondence: [email protected] 1 Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK Full list of author information is available at the end of the article
specific AP-1 members, see Table 1) [47–50]. cJun has since become a major focus for drug discovery, and its terminal activity within a number of pathways makes for a compelling target to ablate oncogenic signals that occur at any signalling level. This review will describe the role of AP-1 in general and how cJun specifically is dysregulated in various cancers. We describe antagonists from the literature, categorised according to the interaction surface within the cJun-DNA complex they target, as potential therapeutics against cJun dysregulation.
AP-1 Structure and Function AP-1 proteins bind to DNA via their basic leucinezipper (bZIP) domain (Fig 1a); comprised of an Nterminal DNA binding d
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