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Proteasome and Protease Inhibitors
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
N. E. Franke, J. Vink, J. Cloos, Gertjan J. L. Kaspers
Mechanisms distinct of the proteasome itself have also been suggested to be involved in bortezomib sensitivity and resistance. A microarray study has shown that overexpression of activating transcription factor (ATF)3, ATF4, ATF5, c-Jun, JunD, and caspase-3 is correlated with bortezomib in B-cell lymphoma cells (89). Furthermore, overexpression of cyclin D1 might also increase bortezomib sensitivity in vitro and in vivo in a breast cancer model (90). In contrast overexpression of heat shock protein (HSP)27, HSP70, HSP90 and T-cell factor 4 is associated with bortezomib resistance in B-cell lymphoma cells (89). These data together suggest that although the proteasome conformation is very important in bortezomib sensitivity, other factors might also be involved in intrinsic and acquired bortezomib resistance.
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Further microarray studies in CYP2D6-humanized transgenic mice have shown that seven transcription factors, namely, activating transcription factor 5 (ATF5), early growth response 1 (EGR1), forkhead box protein A3 (FOXA3), JUNB, KLF9, KLF10, and REV-ERBα, are upregulated in mouse liver during pregnancy (Koh et al. 2014b). KLF9 itself is a weak transactivator of CYP2D6 promoter but significantly enhances CYP2D6 promoter transactivation by HNF-4α, a known transcriptional activator of CYP2D6 expression. The results from deletion and mutation analysis of CYP2D6 promoter activity have identified a KLF9 putative binding motif at the –22/-14 region to be critical in the potentiation of HNF-4α–induced transactivation of CYP2D6 (Koh et al. 2014b). KLF9, a member of the KLF transcription factor family of zinc finger DNA-binding proteins, can either activate or repress target gene expression in a promoter-specific context. KLF9 is involved in cell differentiation of B cells, keratinocytes, and neurons. Biologic actions of KLF9 are mediated either by its direct binding to the promoters of its target genes such as CYPIAI or by coactivation of other transcription factors (Kaczynski et al. 2002; Shields and Yang 1998; Zhang et al. 1998). KLF9 is also a key transcriptional regulator for uterine endometrial cell proliferation, adhesion, and differentiation, all factors that are essential during the process of pregnancy and are switched off during tumorigenesis (Pabona et al. 2012; Shimizu et al. 2010; Simmen et al. 2008, 2015). In endometrial cells, KLF9 binds to progesterone receptors and enhances transcriptional activation of the target genes (Zhang et al. 2003).
Transcriptomic analysis of the Non-Obstructive Azoospermia (NOA) to address gene expression regulation in human testis
Published in Systems Biology in Reproductive Medicine, 2023
Govindkumar Balagannavar, Kavyashree Basavaraju, Akhilesh Kumar Bajpai, Sravanthi Davuluri, Shruthi Kannan, Vasan S. Srini, Darshan S. Chandrashekar, Neelima Chitturi, Kshitish K. Acharya
Based on the averages scores of Closeness, Betweenness, and Degree (Supplemental Table 11), SP1 formed the most conspicuous central node with an average node score of 372 in the network, with 15 potential direct target genes that code for TFs (10) or cTFs (5). Of these 15 potential targets, all of which were down-regulated, seven were known transcription activators. SP1 also seems to be part of a regulatory axis along with HSF4 and RAD51. HSF4 is a known inhibitor of RAD51, which activates SP1 in turn. We hypothesize that the up-regulation of HSF4 and the resulting down-regulation of RAD51 under NOA-testis is one of the causes of SP1 down-regulation, which in turn results in the down-regulation of at least seven other transcription factors. The current results help us to postulate that multiple spermatogenic genes (see Table 2) might be regulated via this regulatory axis, where up-regulation of HSF4 under the NOA condition results in suppression of RAD51 transcription, that, in turn, results in a lack of activation of SP1, thus resulting in the down-regulation of this key TF. CREBBP could also be an important regulator, via RAD51, of SP1. Down-regulation of CREBBP and ATF5, which normally activate CREB1, may also have suppressed CREB1 under the NOA condition, and eventually causing an up-regulation of SNAI2. Another suppressor of this TF, EZH2, is also down-regulated, even though the activating TF for the SNAI2 gene, MTA1, is up-regulated under NOA. The cell-type expression analysis of the TFgenes showed that SP1 and CREBBP are spermatocyte and spermatid enriched in normal adult testis.
Association of human Hedgehog interacting protein gene polymorphisms with the risk of chronic obstructive pulmonary disease: a meta-analysis
Published in Expert Review of Respiratory Medicine, 2022
Yi Liao, Yue Liao, Fuqiang Wen
The HHIP-regulated sonic hedgehog signaling pathway also plays an important role in lung development, especially in early bronchogenesis [37]. Homozygous offspring of HHIP knockout mice die of respiratory failure within a few hours after birth [37]. Kim et al. also found that structural changes in the HHIP protein can affect lung development and self-healing function [38]. The above studies suggest that HHIP may play an important role in maintaining normal lung function. In addition, HHIP deletion affects the gene expression of the membrane-binding protein Reck, which can inhibit the transcription, synthesis and activation of matrix metalloproteinases, including MMP2, MMP7 and MMP9. MMP-9 is the main rate-limiting enzyme regulating the metabolism of the extracellular matrix and has an inflammatory effect on the airway. An imbalance in the ratio of MMP-9 and TIMP-1 in induced sputum was found to be related to asthma, COPD airway inflammation and airflow restriction. MMP-9 and TIMP-1 play a role in extracellular matrix remodeling and airflow restriction [39]. Another target gene of HHIP, BIRC5, is an antiapoptotic protein that interferes with cell death by regulating cysteine-containing aspartate proteolytic enzymes in a dependent and independent manner. After smoking-induced lung injury, HHIP loss leads to decreased expression of FGF2, ATF5 and BIRC5 in cells and promotes apoptosis [40].
The role of CMV in glioblastoma and implications for immunotherapeutic strategies
Published in OncoImmunology, 2019
Maryam Rahman, Farhad Dastmalchi, Aida Karachi, Duane Mitchell
CMV-mediated oncogenesis has also been proposed to be modulated through expression of US28, a virally encoded chemokine receptor. US28 has been found to be expressed in 60% of human GBM samples and can bind several chemokines (CCL2, CCL5, CX3CL1). During CMV infection, US28 has constitutive activity resulting in G-protein dependent signaling. Overexpression of US28 in glioma cells promoted secretion of vascular endothelial growth factor (VEGF)30, activated signal transducer and activator of transcription (STAT)3, and resulted in increased GBM cell invasiveness.31 US28 expression also accelerates glioma growth.32 De Wit et al. found that US28 resulted in activation of hypoxia inducible factor 1alpha/pyruvate kinase M2 (HIF-1alpha/PKM2) in GBM cells which resulted in increased VEGF and lactate secretion.33 Increased proliferation of cells expressing US28 was reversed by inhibiting HIF-1alpha/PKM2. In addition to promoting tumor cellular growth, other groups have found that CMV prevents apoptosis of GBM tumor cells by overexpression of activating transcription factor 5 (ATF5).34