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Huntington’s Disease and Stem Cells
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Karen Ring, Robert O’Brien, Ningzhe Zhang, Lisa M. Ellerby
While the exact mechanisms of HD pathogenesis are unknown, a number of players have been associated with mHtt toxicity. One example is mHtt’s role in transcriptional dysregulation by its interaction with the CREB-binding protein (CBP), which acts as a coactivator of numerous gene promoters in the survival pathway and is necessary for cell function (31,32). The structure of the CBP protein contains 18 glutamines, which interact directly with the glutamine tract in mHtt. Thus, mHtt sequesters CBP and inhibits it from conducting its normal function, which negatively impacts gene transcription and results in neurotoxicity. Another pathway mediating mHtt toxicity is the Rhes protein, which is a small GTPase located specifically in the striatum (33). Rhes directly binds to mHtt and facilitates its sumoylation by acting as an E3 ligase. The sumoylated form of mHtt leads to disaggregation of mHTT and elevates the levels of soluble intracellular mHtt, which leads to neurotoxicity and neurodegeneration. The role of Rhes in HD pathogenesis has been supported with in vivo studies that discovered that HD transgenic mice crossed with Rhes knockout mice had delayed onset of HD symptoms (34).
Role of Krüppel-Like Factors in Endothelial Cell Function and Shear Stress–Mediated Vasoprotection
Published in Juhyun Lee, Sharon Gerecht, Hanjoong Jo, Tzung Hsiai, Modern Mechanobiology, 2021
Of particular importance is the ability of shear-induced KLF2 to mediate the favorable effects of shear stress. Indeed, more than 15% of all flow-regulated genes are dependent on flow-mediated KLF2 induction, and of those most highly regulated by flow, approximately 50% are KLF2 dependent [57]. The Horrevoetts laboratory has suggested that three characteristics of KLF2—(i) potent upregulation by prolonged laminar shear stress, (ii) lack of upregulation by other physiological mediators, and (iii) vascular expression limited to the endothelium—make it an attractive candidate as an integral mediator of laminar flow [45]. Targets of KLF2 (direct or indirect) are involved in mediating a broad range of shear-regulated systemic, cellular, and molecular events. The effect of KLF2 on regulation of the expression of two critical mediators of vascular tone, eNOS and endothelin-1 (ET-1), has been published by several laboratories [29, 46, 57]. As described in detail in earlier chapters, nitric oxide (NO) production in response to shear stress is a fundamental mechanism of regulation of vascular tone. KLF2 is one of the most potent inducers of eNOS expression yet described [29]. Mechanistic studies have revealed that KLF2 directly binds to the eNOS promoter. Furthermore, KLF2 recruits the coactivator CREB-binding protein (CBP)/p300 to the eNOS promoter [29]. KLF2 has also been shown to induce C-natriuretic peptide and arginosuccinate synthase, a limiting enzyme in eNOS substrate bioavailability [44, 46, 65]. Finally, KLF2 reduces the expression of caveolin-1, which negatively regulates eNOS activity [66]. In concert, KLF2 inhibits the expression of adrenomedullin, ET-1, and angiotensin-converting enzyme, all of which increase vascular tone [46]. Surprisingly, the in vivo phenotype of conditional embryonic loss of systemic or endothelial-specific KLF2 is lethal embryonic heart failure, thought to be secondary to low vascular tone [67]. The phenotype, demonstrated in both mice and zebrafish, is rescued by the administration of phenylephrine. A molecular mechanism for the phenotype could not be demonstrated in this study as the expressions of target genes known to affect vascular tone (including eNOS, adrenomedullin, and ET-1, as well as smooth muscle cell function) were similar in the controls and knockout mice. The authors of the study hypothesized that the phenotype is due to the loss of an as yet unidentified gene or is a result of small changes in a large number of known target genes.
Genotoxic effect induced by dried nicotiana tabacum leaves from tobacco barns (kiln-houses) in chinese hamster lung fibroblast cells (V79)
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Daiana Dalberto, Caroline Cardoso Nicolau, Melissa Rosa De Sousa, Ana Letícia Hilário Garcia, Fernanda Boaretto, Jaqueline Nascimento Picada, Guilherme Maurício Soares De Souza, Paola Chytry, Johnny Ferraz Dias, Cleverson Costa Feistel, Alexandre Barros Falcão Ferraz, Ivana Grivicich, Juliana Da Silva
A biological interaction network was constructed from nicotine and inorganic elements detected by PIXE presented 163 nodes and 909 edges. The network substructure with densely connected nodes (clusters) was assessed and 9 clusters visualized with a cutoff score ≥2 (data not shown). The two clusters with the highest scores were Cluster 2 and 6. The clusters possess key bioprocesses associated with cell cycle control, proliferation, differentiation, cell growth and death, cell cycle regulation, transcription factors, signal transduction, drug metabolism. The analysis of the centralities graph demonstrated hubs-bottleneck nodes, the main proteins found being AKT1 (Serine/Threonine Kinase 1), PPP2R1A (Phosphatase 2 Scaffold Subunit Alpha), CREBBP (CREB Binding Protein), CYP1A1 (Cytochrome P450 Family 1 Subfamily A Member 1), EP300 (E1A Binding Protein P300), PPP2CA (Protein Phosphatase 2 Catalytic Subunit Alpha), HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1), CDC5L (Cell Division Cycle 5 Like) (Figure 3).