Glioblastoma (GBM) is the most common form of primary adult brain tumors. A majority of GBMs grow invasively into distant brain tissue, leading to tumor recurrence, which is ultimately incurable. It is, therefore, essential to discover master regulators that control GBM invasiveness and target them therapeutically. We demonstrate here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of GBM cell lines and primary GBM cells. Id-1 expression levels positively correlate with glioma cell invasiveness in culture and with histopathological grades in patient biopsies. Id-1 knockdown dramatically reduces GBM cell invasion that is accompanied by profound morphological changes and robust reduction in expression levels of “mesenchymal” markers, as well as inhibition of self-renewal potential and down-regulation of glioma stem cell markers. Importantly, genetic knockdown of Id-1 leads to a significant increase in survival in an orthotopic model of human GBM. Furthermore, we show that a non-toxic compound, cannabidiol, significantly down-regulates Id-1 gene expression and associated glioma cell invasiveness and self-renewal. Additionally, cannabidiol significantly inhibits the invasion of GBM cells through an organotypic brain slice and glioma progression in vivo. Our results suggest that Id-1 regulates multiple tumor-promoting pathways in GBM, and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of GBM patients.
Genomic sequencing analyses of a variety of human cancers have revealed that massive mutations of cancer-relevant genes are the major alterations in cancerous cells, and their mutation frequencies or rates are highly associated with the development, progression, metastasis, and drug resistance of cancers as well as their clinical outcomes and prognosis. One predominant genetic alternation in human epithelial ovarian cancer (EOC) is the mutation of TP53 that encodes the tumor suppressor p53 protein. This essay will review the most recent progress in understanding the role of TP53 mutations in development, progression, and metastasis of EOC, and discuss the potential of TP53 mutations as diagnostic and prognostic biomarkers as well as therapeutic targets for EOC.
The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials.
The COVID-19 pandemic has greatly affected all of society, including teams in organizational settings. Collaborative teamwork is particularly susceptible to pandemic disruptions, as coordination across individuals becomes challenging in socially distanced and virtual contexts. Unfortunately, COVID-19 research thus far has primarily studied individual health and performance. Analysis of 90 open-ended survey responses gives voice to students working in project teams during the pandemic and provides future research directions regarding the multilevel impacts of the pandemic on teamwork. Results reflect three themes: (1) challenges experienced; (2) changes to team communication, tasks, and roles; and (3) consequences to team progress and outcomes.
LpxC is a deacetylase that catalyzes the first committed step of lipid-A biosynthesis in Escherichia coli. LpxC competes for a common precursor, R-3-hydroxymyristoyl-UDP-GlcNAc, with FabZ, whose dehydratase activity catalyzes the first committed step of phospholipid biosynthesis. To maintain the optimum flow of the common precursor to these two competing pathways, LpxC level is controlled by FtsH/YciM-mediated proteolysis. It is not known whether this complex or another protein senses the status of lipid-A synthesis to control LpxC proteolysis. The work carried out in this study began with a novel mutation yejM1163, which causes hypersensitivity to large antibiotics such as, vancomycin and erythromycin. Isolates resistant to these antibiotics carried suppressor mutations in the ftsH and yciM genes. Western blot analysis showed a dramatically reduced LpxC level in the yejM1163 background, while the presence of ftsH or yciM suppressor mutations restored LpxC levels to different degrees. Based on these observations, it is proposed that YejM is a sensor of lipid-A synthesis and controls LpxC levels by modulating the activity of the FtsH/YciM complex. The truncation of the periplasmic domain in the YejM1163 protein causes unregulated proteolysis of LpxC, thus diverting a greater pool of R-3-hydroxymyristoyl-UDP-GlcNAc towards phospholipid synthesis. This imbalance in lipid synthesis perturbs the outer membrane permeability barrier, causing hypersensitivity towards vancomycin and erythromycin. yejM1163 suppressor mutations in ftsH and yciM lower the proteolytic activity towards LpxC, thus restoring lipid homeostasis and the outer membrane permeability barrier. Importance Lipid homeostasis is critical for proper envelope functions. The level of LpxC, which catalyzes the first committed step of LPS synthesis, is controlled by an essential protease complex comprised of FtsH and YciM. Work carried out here suggests YejM, an essential envelope protein, plays a central role in sensing the state of LPS synthesis and controls LpxC levels by regulating the activity of FtsH/YciM. All four essential proteins are attractive targets of therapeutic development.
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