Author : Mario Ramiro Calderon
Release : 2013
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Kind : eBook
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Book Synopsis Identification and Characterization of Novel Functional Interactions of Ligand-dependent CoRepressor by : Mario Ramiro Calderon

Download or read book Identification and Characterization of Novel Functional Interactions of Ligand-dependent CoRepressor written by Mario Ramiro Calderon. This book was released on 2013. Available in PDF, EPUB and Kindle. Book excerpt: "Gene transcription is highly regulated by proteins called transcription factors, which bind to specific DNA sequences, and recruit a plethora of cofactors that directly modify the chemical composition of N-terminal histone tails or recruit enzymes that do so. These modifications alter the structure of chromatin, and can prime it for or render it refractory to transcription. Many of these recruited cofactors, termed transcriptional coactivators or corepressors, can interact with several classes of transcription factors. Initially characterized as an inhibitor of nuclear receptor-mediated transactivation, Ligand-dependent CoRepressor (LCoR) represses transcription through recruitment of specific C-terminal binding proteins (CtBPs) and histone deacetylases (HDACs) via defined domains. We were interested in determining whether LCoR also serves as a coregulator of other classes of transcription factors. Using yeast two-hybrid screens with the open reading frame of LCoR as bait, we found novel interactions with the transcription factor Krüppel-like factor 6 (KLF6) and another transcriptional coregulator Krüppel-Associated Box (KRAB)-associated protein 1 (KAP-1). KLF6 may act as a tumour suppressor in certain malignancies, while KAP-1 is a corepressor that functions through many zinc finger transcription factors. Functional characterization of these interactions revealed that LCoR regulates the expression of the genes cyclin-dependent kinase inhibitor 1A (CDKN1A) and cadherin 1 (CDH1) in specific prostate cancer cells via KLF6, and growth arrest and DNA-damage-inducible alpha (GADD45A) and fibroblast growth factor 2 (FGF2) in specific breast cancer cells through KAP-1. CDKN1A expression is regulated by the hormone insulin-like growth factor 1 (IGF-1) in certain cell types, and levels of IGF-1 and CDKN1A are elevated in prostate cancer. We found that LCoR and CDKN1A levels were enhanced in prostate cancer tissue and in IGF-1 treated prostate cancer cells. Additionally, the transcriptional response of a complex composed of KLF6 and LCoR may be altered by IGF-1 as we found that treatment of prostate cancer cells transiently overexpressing KLF6 and LCoR with IGF-1 abrogated their repression of a reporter gene. Hence, IGF-1-mediated transcriptional expression of CDKN1A may occur through KLF6 and LCoR and have implications for prostate cancer development. Similarly, the expression of FGF2 is frequently lost and associated with a more malignant phenotype in breast cancer. Our results show that a transcriptional complex composed of LCoR, KAP-1, and the transcription factor ZBRK1 suppresses the expression of the FGF2 gene in breast cancer cells, which enhanced cell viability. The identification of this transcriptional silencing complex provides a mechanism for the lack of expression of FGF2 in breast cancer. The work presented in this thesis contains four major contributions to further the understanding of the biological function of LCoR. In addition to identifying novel molecular interactions with (1) KLF6 and (2) KAP-1, which illustrate that LCoR can function in transcription independent of nuclear receptors, the functional characterization of these interactions revealed potential roles for LCoR in (3) breast and (4) prostate tumour development." --