The Dishevelled gene was first identified in Drosophila mutants with disoriented hair and bristle polarity [1-3]. The Dsh gene (Dsh/Dvl, in Drosophila and vertebrates respectively) gained popularity when it was discovered that it plays a key role in segment polarity during early embryonic development in Drosophila [4]. Subsequently, the vertebrate homolog of Dishevelled genes were identified in Xenopus (Xdsh), mice (Dvl1, Dvl2, Dvl3), and in humans (DVL1, DVL2, DVL3) [5-10]. Dishevelled functions as a principal component of Wnt signaling pathway and governs several cellular processes including cell proliferation, survival, migration, differentiation, polarity and stem cell renewal. This review will revisit seminal discoveries and also summarize recent advances in characterizing the role of Dishevelled in both normal and pathophysiological settings.
SIRT1, an NAD+-dependent deacetylase, has been described in the literature as a major player in the regulation of cellular stress responses. Its expression has been shown to be altered in cancer cells, and it targets both histone and non-histone proteins for deacetylation and thereby alters metabolic programs in response to diverse physiological stress. Interestingly, many of the metabolic pathways that are influenced by SIRT1 are also altered in tumor development. Not only does SIRT1 have the potential to regulate oncogenic factors, it also orchestrates many aspects of metabolism and lipid regulation and recent reports are beginning to connect these areas. SIRT1 influences pathways that provide an alternative means of deriving energy (such as fatty acid oxidation and gluconeogenesis) when a cell encounters nutritive stress, and can therefore lead to altered lipid metabolism in various pathophysiological contexts. This review helps to show the various connections between SIRT1 and major pathways in cellular metabolism and the consequence of SIRT1 deregulation on carcinogenesis and lipid metabolism.
Background The long history of distrust that characterizes the relationship between the Black/African-American population and the US Medical community makes COVID-19 vaccine hesitancy of great concern. A needs assessment of the Black/African-American community assessed willingness and explored the perceptions of community members regarding COVID-19 vaccination. Methods The study used a mixed-methods approach. Respondents ( n = 183) were surveyed with a web-based questionnaire. They were asked whether there would get vaccinated for COVID-19 barring any access or cost-related challenges. Perceptions of community members regarding vaccination were explored through one-on-one interviews ( n = 30) and eight focus groups ( n = 49), with participants drawn from across various demographic characteristics. Survey responses were summarized using frequencies and proportions. A thematic analysis was conducted on the qualitative data. Results Thirty-four percent of respondents indicated “Yes” (willing to get vaccinated); 26.8% indicated “No”, while 37.1% expressed hesitancy (“Maybe” or “I don’t know”). Themes emerging from the qualitative data are grouped into three broad categories: vaccine accessibility (transportation, information, navigating healthcare system); vaccine hesitancy (with sub-categories of compliance, complacency and confidence); and vaccine “resistance” (conspiracy theories, conflicting beliefs, distrust of Government, trustworthiness of Health care). Conclusion Findings demonstrate a nuanced expansion of “vaccine hesitancy” to delineate groups with varying issues and perspectives. Interventions to enhance vaccination rates in Black/African-American communities should incorporate components that assure accessibility at the minimum, but also address non-access-related issues. Priority should be given to enhancing vaccine literacy, information-sharing as efficacy and safety data emerge, and addressing specific concerns identified through community-engaged outreach efforts.
The Wnt signaling pathway is often chronically activated in diverse human tumors, and the Frizzled (FZD) family of receptors for Wnt ligands, are central to propagating oncogenic signals in a β-catenin-dependent and independent manner. SIRT1 is a class III histone deacetylase (HDAC) that deacetylates histone and non-histone proteins to regulate gene transcription and protein function. We previously demonstrated that SIRT1 loss of function led to a significant decrease in the levels of Dishevelled (Dvl) proteins. To further explore this connection between the sirtuins and components of the Wnt pathway, we analyzed sirtuin-mediated regulation of FZD proteins. Here we explore the contribution of sirtuin deacetylases in promoting constitutive Wnt pathway activation in breast cancer cells. We demonstrate that the use of small molecule inhibitors of SIRT1 and SIRT2, and siRNA specific to SIRT1, all reduce the levels of FZD7 mRNA. We further demonstrate that pharmacologic inhibition of SIRT1/2 causes a marked reduction in FZD7 protein levels. Additionally, we show that β-catenin and c-Jun occupy the 7 kb region upstream of the transcription start site of the FZD7 gene, and SIRT1 inhibition leads to a reduction in the occupancy of both β-catenin and c-Jun at points along this region. This work uncovers a new mechanism for the regulation of FZD7 and provides a critical new link between the sirtuins and FZD7, one of the earliest nodal points from which oncogenic Wnt signaling emanates. This study shows that inhibition of specific sirtuins may provide a unique strategy for inhibiting the constitutively active Wnt pathway at the level of the receptor.
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