The Scientific Basis of Medicine
John S. Axford, Chris A. O'Callaghan in Medicine for Finals and Beyond, 2023
An effective mechanism is required to remove cells that are damaged or no longer necessary. This programmed cell death is generally known as apoptosis (Figure 2.7), and follows a carefully controlled series of events allowing the cell to condense its cytoskeleton and fragment its DNA. Apoptosis is driven by members of the caspase protein family. Bcl proteins regulate caspase activity. Programmed cell death can be triggered in response to stimuli such as cell surface signals or mitochondrial stress. Following ligand binding, cell-surface death receptors such as Fas recruit adaptor proteins to trigger procaspase activation, and thus elicit apoptosis. Mitochondria can initiate an alternative apoptotic pathway in response to DNA damage or intracellular oxidative stress. A dying cell will show membrane blebbing, cell shrinkage and protein fragmentation as it collapses in upon itself. Within the nucleus, chromatin condensation and DNA degradation occur. Finally, the cell is flagged for uptake by phagocytic cells.
Role of Nonhistone Chromosomal Proteins in Selective Gene Expression
Gerald M. Kolodny in Eukaryotic Gene Regulation, 2018
The contractile proteins actin, myosin, and tropomyosin have been identified in the chromatin of the lower eukaryotes Physarum polycephalum278,279 and Dictyostelium discoideum280,281 and also in mammalian cells such as HeLa,279 rat liver,282 and mouse embryo fibroblasts.283 However, there is currently a controversy about the possibility that the nuclear actin may be due to cytoplasmic contamination during nuclear preparation”4 or to the random distribution of actin within the cell.284 If these contractile proteins are true components of chromatin, they may well have a role in chromatin condensation. Other possible roles for these proteins are the transport of RNA from the nucleus to the cytoplasm or, through the ability of actin to specifically bind and inactivate DNase I,285 the long-term preservation of the genome in cysts or spores.
Anti-Cancer Agents from Natural Sources
Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg in Promising Drug Molecules of Natural Origin, 2020
Cytolethal distending toxins (CDTs) are a type of heterotrimeric toxins, produced by specific gram-negative mucocutaneous bacteria (Jinadasa et al., 2011). CDTs are AB-type toxins with DNase potential, which allows them to penetrate the targeted cell’s DNA (Guerra et al., 2011). They are primarily composed of cdtA, cdtB, and cdtC subunits. Because of this reason, it has been studied constantly to fully understand the mechanistic pathways in cancer cells. Bachran et al. (2014) extracted CdtB from Haemophilus ducreyi and fused it to the N-terminal 255 amino acids of Bacillus anthracis toxin lethal factor (LFn) to determine its (LFnCdtB) anti-malignant character. LFnCdtB showed its ability to inhibit proliferation of several human cancerous cells by arresting cell cycle in the G2/M phase, followed by apoptosis. In LLC model, the cytotoxicity was moderate to low. Further study on A549 adenocarcinoma was reported by Yaghoobi et al. (2016). A combined formulation of pcDNA3.1, an expression vector and cdtB derived from Aggregatibacter actinomycetemcomitans was applied in A549 cells. Apoptosis was noted through caspase-9 activation. Cells evaluated with pcDNA3.1 alone demonstrated 16.5%cell death whereas the cells evaluated with pcDNA3.1/cdtB demonstrated about four-fold higher (63.4%) rate of cell death through apoptosis. Morphological changes were also observed by chromatin condensation, which changed the shape of cancer cells. Growth and proliferation were notably inhibited in a time-dependent manner when pcDNA3.1/cdtB combination was used.
Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets
Published in Expert Opinion on Therapeutic Targets, 2022
Alberto Zambelli, Riccardo Sgarra, Rita De Sanctis, Elisa Agostinetto, Armando Santoro, Guidalberto Manfioletti
DNA methyltrasferase 1 (DNMT1) is the most crucial enzyme in the DNMTs family in humans and it is highly expressed in TNBC compared to other subtypes [128]. Notably, a preclinical study suggests that DNMT inhibitors such as 5-azacytidine can increase the efficacy of PARP inhibitors in BC cells with wild-type BRCA1 [129]. Moreover, hypomethylating agents might play a role in selected cases of breast cancer with sporadic abnormally BRCA1 gene promoter methylation [130]. The HDACs are a class of enzymes that deacetylate histones leading to chromatin condensation, repressing transcription. Therefore, HDAC inhibitors could induce tumor cell apoptosis, inhibit cell migration and invasion and sensitize cancer cells to chemotherapy [131]. Preclinical and clinical studies with HDAC inhibitors in combination with other drugs showed promising results in TNBC [125]. Another relevant candidate target, which is involved in chromatin regulation, is the architectural chromatin family of high mobility group A proteins (HMGA). Indeed, HMGA are overexpressed in cancers, regulate chromatin plasticity and, in TNBC, can act as master regulators of genes involved in epithelial-to-mesenchymal transition, migration, invasion, and angiogenesis [132,133].
Ultra-long silver nanowires induced mitotic abnormalities and cytokinetic failure in A549 cells
Published in Nanotoxicology, 2019
Fengbang Wang, Ying Chen, Yuanyuan Wang, Yongguang Yin, Guangbo Qu, Maoyong Song, Hailin Wang
As major regulator of mitosis, p-Histone 3 (ser10) and Aurora A are responsible for precisely spatiotemporal segregation of the duplicated chromosomes at different stages. Histone 3 (ser10) phosphorylation is reported to drive chromatin condensation by regulating other protein interactions in the initial stage and plays a coordinating role in exact segregation of chromosomes (Hendzel et al. 1997). As a kinase, Aurora A was found efficiently phosphorylate the Histone 3 (ser10) through direct interaction in vitro and in vivo (Crosio et al. 2002). At first, Aurora A accumulated at the centrosomes and then highly localized to the mitotic spindles at prophase and metaphase (Marumoto et al. 2003; Marumoto, Zhang, and Saya 2005). The two factors are keys to the fidelity of early and late mitotic events as their overexpression could result in multinucleation, centrosome amplification, and even cancer (Meraldi, Honda, and Nigg 2002; Ohishi et al. 2010). One of our assumptions is that ultra-long AgNWs induced the aberrant upregulation of p-Histone 3 (ser10) and Aurora A, and then the upregulation results in centrosome amplification and further mitotic abnormality.
Targeting transcription factors in multiple myeloma: evolving therapeutic strategies
Published in Expert Opinion on Investigational Drugs, 2019
Shirong Li, Sonia Vallet, Antonio Sacco, Aldo Roccaro, Suzanne Lentzsch, Klaus Podar
Histone acetylation is regulated by either histone deacetylases (HDACs) or by histone lysine acetyltransferases (KATs: type A, type B). Histone acetylation neutralizes the positive charge of lysines, thereby opening the chromatin structure, reducing the interaction of histones with negatively charged DNA, and ultimately increasing transcriptional activity. Moreover, acetylated histones provide binding sites for BET proteins, which additionally induce transcriptional activity. In contrast, histone deacetylation is associated with chromatin condensation and transcriptional repression. MM is also associated with an increase of HDAC levels resulting in a less condensed chromatin structure, enhanced transcriptional activity of signal-activated TFs, and adverse prognosis [134]. Approaches to target histone acetyltransferases include the CBP/p300 inhibitors SGC-CBP30, I-CBP112, and A-485 [40].