Human MCS5A1 candidate breast cancer susceptibility gene FBXO10 is induced by cellular stress and correlated with lens epithelium-derived growth factor (LEDGF)

Abstract

Genetic variation and candidate genes associated with breast cancer susceptibility have been identified. Identifying molecular interactions between associated genetic variation and cellular proteins may help to better understand environmental risk. Human MCS5A1 breast cancer susceptibility associated SNP rs7042509 is located in F-box protein 10 (FBXO10). An orthologous Rattus norvegicus DNA-sequence that contains SNV ss262858675 is located in rat Mcs5a1, which is part of a mammary carcinoma susceptibility locus controlling tumor development in a non-mammary cell-autonomous manner via an immune cell-mediated mechanism. Higher Fbxo10 expression in T cells is associated with Mcs5a increased susceptibility alleles. A common DNA-protein complex bound human and rat sequences containing MCS5A1/Mcs5a1 rs7042509/ss262858675 in electrophoretic mobility shift assays (EMSAs). Lens epithelium-derived growth factor (LEDGF), a stress-response protein, was identified as a candidate to bind both human and rat sequences using DNA-pulldown and mass spectrometry. LEDGF binding was confirmed by LEDGF-antibody EMSA and chromatin immunoprecipitation (ChIP). Ectopic expression of LEDGF/p75 increased luciferase activities of co-transfected reporters containing both human and rat orthologs. Over-expressed LEDGF/p75 increased endogenous FBXO10 mRNA levels in Jurkat cells, a human T-cell line, implying LEDGF may be involved in increasing FBXO10 transcript levels. Oxidative and thermal stress of Jurkat cells increased FBXO10 and LEDGF expression, further supporting a hypothesis that LEDGF binds to a regulatory region of FBXO10 and increases expression during conditions favoring carcinogenesis. We conclude that FBXO10, a candidate breast cancer susceptibility associated gene, is induced by cellular stress and LEDGF may play a role in expression of this gene.

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

“…However, in this study and another study by one of our laboratories, we find that translated cFos can bind to the distal site as either a homodimer or a monomer (Xu et al, 2014). We showed that tBHQ-induced expression of CYP2C9 is mediated possibly by interaction between cFos and JunD on different AP-1 sites.…”

Roles of F-box proteins in cancer

“…65). In support of this notion, there is pathological evidence indicating that low expression levels of FBXO10 were tightly associated with breast cancer risk 66–68 . Similarly, FBXO18 is often deleted or mutated in melanoma cells, and the depletion of FBXO18 enhances ultraviolet (UV)-mediated transformation of human melanocytes, which suggests a tumoursuppressive role of FBXO18 (REF.…”

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

“…In addition, LEDGF/p52 has been associated with splicing through its interaction with serine/arginine-rich splicing factor 1 (SRSF1) 1,5 . Currently it is not clear whether the previously proposed roles of LEDGF/p75 in apoptosis and stress response, as well as its increased expression levels in different cancer types, are related to one of these functions [6][7][8][9][10][11] .…”