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Ta H.Q.,Immunology and Cancer Biology | Gioeli D.,Immunology and Cancer Biology | Gioeli D.,University of Virginia
Endocrine-Related Cancer | Year: 2014

It is increasingly clear that castration-resistant prostate cancer (PCa) is dependent on the androgen receptor (AR). This has led to the use of anti-androgen therapies that reduce endogenous steroid hormone production as well as the use of AR antagonists. However, the AR does not act in isolation and integrates with a milieu of cell-signaling proteins to affect cell biology. It is well established that cancer is a genetic disease resulting from the accumulation of mutations and chromosomal translocations that enables cancer cells to survive, proliferate, and disseminate. To maintain genomic integrity, there exists conserved checkpoint signaling pathways to facilitate cell cycle delay, DNA repair, and/or apoptosis in response to DNA damage. The AR interacts with, affects, and is affected by these DNA damage-response proteins. This review will focus on the connections between checkpoint signaling and the AR in PCa. We will describe what is known about how components of checkpoint signaling regulate AR activity and what questions still face the field. © 2014 Society for Endocrinology Source

Koryakina Y.,Immunology and Cancer Biology | Ta H.Q.,Immunology and Cancer Biology | Gioeli D.,Immunology and Cancer Biology | Gioeli D.,University of Virginia
Endocrine-Related Cancer | Year: 2014

The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as a transcription factor but also as a node that integrates multiple extracellular signals. The AR plays an important role in many diseases, including complete androgen insensitivity syndrome, spinal bulbar muscular atrophy, prostate and breast cancer, etc. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Greater understanding of the molecular mechanisms involved in AR action will enable the development of improved therapeutics to treat the wide range of AR-dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine, and tyrosine residues. In this paper, we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed. © 2014 Society for Endocrinology. Published by Bioscientifica Ltd. Source

Moreau G.B.,Immunology and Cancer Biology | Mann B.J.,Immunology and Cancer Biology
Virulence | Year: 2013

Francisella tularensis is a highly virulent bacterial pathogen that is easily aerosolized and has a low infectious dose. As an intracellular pathogen, entry of Francisella into host cells is critical for its survival and virulence. However, the initial steps of attachment and internalization of Francisella into host cells are not well characterized, and little is known about bacterial factors that promote these processes. This review highlights our current understanding of Francisella attachment and internalization into host cells. In particular, we emphasize the host cell types Francisella has been shown to interact with, as well as specific receptors and signaling processes involved in the internalization process. This review will shed light on gaps in our current understanding and future areas of investigation. Source

Johnson J.M.,Immunology and Cancer Biology | Li M.,Immunology and Cancer Biology | Smith J.S.,Immunology and Cancer Biology | French S.L.,University of Virginia | And 3 more authors.
Molecular and Cellular Biology | Year: 2013

Ribosomal DNA (rDNA) genes in eukaryotes are organized into multicopy tandem arrays and transcribed by RNA polymerase I. During cell proliferation, ~50% of these genes are active and have a relatively open chromatin structure characterized by elevatedaccessibility to psoralen cross-linking. In Saccharomyces cerevisiae, transcription of rDNA genes becomes repressed and chromatin structure closes when cells enter the diauxic shift and growth dramatically slows. In this study, we found that nucleosomes are massively depleted from the active rDNA genes during log phase and reassembled during the diauxic shift, largely accounting for the differences in psoralen accessibility between active and inactive genes. The Rpd3L histone deacetylase complex was required for diauxic shift-induced H4 and H2B deposition onto rDNA genes, suggesting involvement in assembly or stabilization of the entire nucleosome. The Spt16 subunit of FACT, however, was specifically required for H2B deposition, suggesting specificity for the H2A/H2B dimer. Miller chromatin spreads were used for electron microscopic visualization of rDNA genes in an spt16 mutant, which was found to be deficient in the assembly of normal nucleosomes on inactive genes and the disruption of nucleosomes on active genes, consistent with an inability to fully reactivate polymerase I (Pol I) transcription when cells exit stationary phase. © 2013, American Society for Microbiology. All Rights Reserved. Source

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