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Cell Biology for Bioprocessing
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
An important cell cycle checkpoint occurs during the transition from G1 to S phase. The pivotal players in the G1/S phase transition are the regulatory retinoblastoma protein (Rb) and the Cdk4/6-Cyclin D complex (i.e., G1-Cdk complex) (Figure 2.20). In growth-arrested or quiescent cells, Rb is unphosphorylated and binds to and inhibits its E2F. E2F is a transcription factor that activates the transcription of Cyclin E and other proteins for S phase. When in a Rb bound state, it suppresses their transcription. Upon stimulation of mitogen and other cues, ERK (a pivotal player of the growth regulatory signaling system) activates the G1-Cdk complex (via a transcription factor like c-Myc) to phosphorylate Rb. The phosphorylated Rb dissociates from E2F, leading to the activation of expression of Cyclin E that in turn drives Cdk2 activation and the formation of cyclin E-Cdk2 (G1/S Cdk complex). E2F positive feedback on the phosphorylation of Rb causes hyperphosphorylation of Rb and activation of Cdk2. The S phase cyclin, Cyclin A, begins to accumulate in late G1 phase, but is bound by an inhibitor. The G1-Cdk complex facilitates the removal of the inhibition to enable the accumulation of S-Cdk complexes, marking the entry into S phase.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The above-mentioned hypomethylation promotes the malignant degeneration of cells due to favoring a reorganization of chromosomal sections. The most important mechanism of epigenetic regulation is the methylation of DNA by DNA-methyltransferases. It has been found that hypermethylation (methylation of cytosine residues of DNA) of gene-promoter regions, leading to transcriptional repression of tumor suppressor genes the protein products of which such as CDK-inhibitor 2A and RB1 (retinoblastoma protein) decelerate tumor progression, is a common feature of many cancers (Baylin and Jones, 2011). This also holds for global deacetylation. Histone deacetylases (HDACs) class I, II, and IV are Zn2+-dependent amidohydrolases removing an acetyl moiety from a lysine residue at the N-terminus of histone. Class III HDACs (sirturins) are NAD+-dependent. The catalytic action of HDACs enables the histones to wrap the DNA more tightly whereas acetylation of histones by acetyl transferases (HATs) transferring an acetyl group from acetyl-CoA to form ε-N-acetyl lysine normally results in an increase in gene expression, e.g., that of the tumor suppressor p53. Various HAT families are known that differ from each other in their reaction mechanism. The equilibrium of histone acetylation and deacetylation is important for a proper modulation of chromatin topology and regulation of gene transcription. For an excellent review of exploiting the epigenome to control cancer-promoting gene-expression programs, see Brien et al. (2016).
Illuminating the cycle of life
Published in Raquel Seruca, Jasjit S. Suri, João M. Sanches, Fluorescence Imaging and Biological Quantification, 2017
Anabela Ferro, Patrícia Carneiro, Maria Sofia Fernandes, Tânia Mestre, Ivan Sahumbaiev, João M. Sanches, Raquel Seruca
Likewise, regulation of the cell cycle on viral infections has been addressed for decades with the aim to identify potential antiviral therapeutic targets. Indeed, viruses target critical cell-cycle regulators and employ several strategies to modulate cell proliferation in order to replicate more efficiently [109]. The most virulent human pathogen causing influenza in humans, influenza A virus (IAV), was reported to induce a G0/G1 arrest and to affect the expression profile of key cell-cycle regulators. Through flow cytometry analysis of the cell cycle, he and colleagues demonstrated that the levels of hyperphosphorylated retinoblastoma protein (Rb) and cyclins E and D1 were decreased, whereas there was a significant increase of p21, consistent with the G0/G1 arrest profile. Furthermore, these alterations were associated with increased viral protein expression and viral progeny production, awarding biological relevance to the interference in the host cell cycle [110].
Ozone ultrafine bubble water induces the cellular signaling involved in oxidative stress responses in human periodontal ligament fibroblasts
Published in Science and Technology of Advanced Materials, 2019
Anongwee Leewananthawet, Shinichi Arakawa, Tokuju Okano, Ryo Daitoku Kinoshita, Hiroshi Ashida, Yuichi Izumi, Toshihiko Suzuki
In RNA-seq analysis, we identified the several differentially expressed genes in OUFBW-treated cells. The most up-regulated metallothionein-1G is a member of intracellular cysteine-rich, metal-binding proteins. Metallothioneins are involved in the array of protective stress responses against various stimuli including oxidative stress [18]. The genes coding metallothioneins have many response elements for up-regulation of transcription in its promoter region that includes ARE. The transcription factor Nrf2 can bind ARE to induce cytoprotective responses to oxidative stress [16]. Therefore, the results suggest the possibility of Nrf2-mediated up-regulation of metallothioneins, which may play a role in protective stress responses against OUFBW stimulation. On the other hand, transcription factor HES1 has been reported to cooperate with retinoblastoma protein to activate transcription factor RUNX2, which is required for osteoblast differentiation and bone formation [22,23]. It may be possible that up-regulated HES1 is involved in osteoblast differentiation in periodontal ligaments. Furthermore, the c-Fos up-regulation in RNA-seq analysis is consistent with the activation MAPK pathway and the nuclear translocation of c-Fos in our study.
Molecular toxicology and carcinogenesis of fumonisins: a review
Published in Journal of Environmental Science and Health, Part C, 2020
Ruth Nabwire Wangia-Dixon, Kizito Nishimwe
The disruption results in accumulation of intracellular free sphinganine, which is linked to alteration of the sphinganine to sphingosine ratio and forms a basis for a biomarker of fumonisin.41 Furthermore, a close relationship on the role of sphinganine accumulation on liver and kidney toxicity has been widely studied and discussed.54,55 Once accumulated, free sphingolipid bases persist in the kidneys much longer than fumonisin B1, which supports the claim that the kidneys are ultimately more sensitive to fumonisin toxicity compared to other organs.12,28,55 Overall, fumonisin-induced increases in free sphingolipid bases and toxicity are both reversible, and elimination of free Sphinganine was faster in liver compared to kidneys of rodents.12,28,55 A portion of the accumulated Sphinganine is metabolized to Sa- 1- phosphate (SaP) and then cleaved into a fatty aldehyde and ethanolamine phosphate.11,56 Sphingolipids are involved in signaling pathways, cell recognition and modulating interactions with receptors and integrin.11,13,57 Other consequences associated with disruption of de novo synthesis pathway of sphingolipid metabolism include inhibition of the protein kinase C, activation of phospholipase D, inhibition of Na+/K+ATPase and induction of dephosphorylation of retinoblastoma protein.11,58,59 Ultimately, once complex sphingolipid are depleted, inhibition of cell growth occurs and ultimately induction of apoptosis.59
Overview of biological mechanisms of human carcinogens
Published in Journal of Toxicology and Environmental Health, Part B, 2019
Nicholas Birkett, Mustafa Al-Zoughool, Michael Bird, Robert A. Baan, Jan Zielinski, Daniel Krewski
Liver flukes produce histopathological changes characterized by inflammation, hyperplasia and metaplasia with a high frequency of changes in the bile duct. Liver flukes excrete various metabolic products that are highly immunogenic. These organisms elevate cell proliferation through stimulation of the retinoblastoma protein Rb and cyclin D1. The immune response leads to endogenous production of NDMA and nitric oxide (NO) and to nitrosation of amines. Liver-fluke infection is linked to diffuse nitrosative and oxidative DNA damage and adduct formation. There is little evidence to support any direct genetic or epigenetic effects.