Showing papers by "Peter D. Adams published in 2008"
TL;DR: Stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.
155 citations
TL;DR: This study has identified individual host factors that maintain retroviral silencing and supports the proposal that these factors participate in an antiviral response and indicates that siRNAs can be used as specific reagents to interrupt the maintenance of epigenetic silencing.
Abstract: Integrated retroviral DNA is subject to epigenetic gene silencing, resulting in loss of expression of viral genes as well as reporter or therapeutic genes transduced by retroviral vectors. Possible mediators of such silencing include the histone deacetylase (HDAC) family of cellular proteins. We previously isolated HeLa cell populations that harbored silent avian sarcoma virus-based green fluorescent protein (GFP) vectors that could be reactivated by treatment with HDAC inhibitors. Here, we developed a small interfering RNA (siRNA)-based approach to identify specific host factors that participate in the maintenance of silencing. Knockdown of HDAC1, the transcriptional repressor Daxx (a binding partner of HDAC1), or heterochromatin protein 1 gamma resulted in robust and specific GFP reporter gene reactivation. Analyses of cell clones and diverse GFP vector constructs revealed that the roles of HDAC1 and Daxx in retroviral silencing are largely independent of the integration site or the promoter controlling the silent GFP reporter gene. Previous findings from our laboratory and those of others have suggested that Daxx and HDAC proteins may act broadly as part of an antiviral response to repress viral gene transcription. Expression of presumptive viral "countermeasure" proteins that are known to inhibit Daxx or HDACs (pp71, IE2, and Gam1) resulted in the reactivation of GFP reporter gene expression. This study has identified individual host factors that maintain retroviral silencing and supports the proposal that these factors participate in an antiviral response. Furthermore, our results indicate that siRNAs can be used as specific reagents to interrupt the maintenance of epigenetic silencing.
54 citations
TL;DR: It is proposed that two early benign neoplasms found in different tissues and which are not generally thought to be similar result from an ongoing ‘tug of war’ between the tumor suppression barrier posed by cellular senescence and the tumor-promoting activity of Wnt signaling.
Abstract: Studies of early neoplasia have revealed fundamental molecular pathways that drive tumorigenesis. Despite this progress, synthesis of principles of tumorigenesis that span tissue types has lagged. Such forays into the 'comparative anatomy' of cancer can stimulate new models and refine key questions. We envision commonality of pathways important in formation of two early benign neoplasms that are found in different tissues and which are not generally thought to be similar: dysplastic nevi of the skin and intestinal aberrant crypt foci. We propose that these neoplasms result from an ongoing 'tug of war' between the tumor suppression barrier posed by cellular senescence and the tumor-promoting activity of Wnt-signaling. Whether or not such neoplasms progress to malignancy or persist in a benign state for many years might be largely determined by the outcome of this tug of war and its modulation by other genetic and epigenetic alterations, such as inactivation of p16(INK4a).
26 citations