Date

2017-06-24

Author

Muyan, Mesut

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Estradiol (E2), the main estrogen hormone in circulation, is involved in the physiological regulation of many organs and tissues, including mammary tissue. E2 also plays a critical role in the initiation and development of breast cancer. Effects of E2 on cells are mediated by estrogen receptor (ER), which is a ligand-dependent transcription factor. Upon binding to E2, ER regulates the expression of target genes through genomic signaling pathways that result in alterations of cellular responses. The interaction of the E2-ER complex with specific DNA sequences, estrogen response elements (EREs), constitutes the initial stage of the EREdependent genomic signaling pathway. The functional interaction of E2-ER with other transcription factors bound to their cognate response elements signifies the ERE-independent genomic signaling route. The expression of estrogen responsive genes mediated by E2-ER encompasses proteins involved in the metabolism of nucleic acid/proteins, transcription factors, membrane signaling cascade and receptor proteins. These proteins in turn participate in the regulation of secondary gene expressions responsible for DNA repair, cell cycle and division and, consequently, in the initiation of E2-mediated cellular proliferation. The identification of E2 responsive genes, characterization of mechanism of gene expressions and discerning functions of protein products could lead to important gains towards understanding of the physiology and pathophysiology of estrogen signaling. Our previous studies indicated that CXXC5 is an estrogen responsive gene. Although, the structure and function of CXXC5 are largely unknown, due to the presence of a zincfinger domain-CXXC domain (ZF-CXXC), CXXC5 is presumed to be a member of the ZF-CXXC protein family. The binding of ZF-CXXC proteins to CpG dinucleotides is suggested to prevent cytosine methylation leading to the formation of a nucleation site for the direct or indirect recruitment of histone modifying proteins to DNA for transcription regulation. We therefore predicted that CXXC5, synthesized as the primary response gene product, participates as an epigenetic factor in the regulation of E2-mediated cellular processes. Our recent studies further indicated that the expression of the estrogen responsive CXXC5 gene is mediated by the E2 bound ER through a direct interaction with an ERE sequence present at the upstream region of the first encoding methionine in the CXXC5 gene locus that results in alterations in CXXC5 protein levels in the nucleus of a cell model. Moreover, we found that CXXC5 is indeed a CpG dinucleotide binding protein. Furthermore, our studies using proximity biotinylation assay, BioID, coupled to LC-MS/MS revealed that CXXC5 putatively interacts with a number of proteins involved in the chromatin remodeling, DNA repair and cell cycle. Our ongoing studies aimed at the verification of protein-partner interactions with the use of various in vitro and in cellula approaches would be supportive for our prediction that CXXC5 as an epigenetic factor is involved in E2-mediated cellular events.

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http://hibit2017.ii.metu.edu.tr/wordpress/wp-content/uploads/HIBIT2017_Conference_Book.pdf
https://hdl.handle.net/11511/79300

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Department of Biology, Conference / Seminar