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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
Additional investigation of the mechanism of flow-induced KLF2 expression has demonstrated that the MEK5/ERK5/MEF2 signaling pathway mediates the increase of KLF2 by laminar shear stress. Kumar and colleagues showed that a single consensus MEF2 binding site in the conserved region of the KLF2 promoter regulates KLF2 promoter activity [28]. ERK5 (also referred to as big mitogen-activated protein kinase-1 [MAPK1] or BMK1) is highly induced by laminar shear stress, and MEF2 is a well-characterized target gene of ERK5. Winoto and colleagues found that ERK5 plays a crucial role in KLF2 expression in embryos and that MEF2 mediates ERK5-induced KLF2 expression [56]. Building on these observations, Parmar et al. demonstrated that dominant-negative MEF2 or mutant MEK5 (an upstream activator of ERK5) abolished flow-mediated KLF2 induction in endothelial cells [57]. Young et al. demonstrated that the shear stress–regulated factor AMP-activated protein kinase is also able to activate the ERK5/MEF2 pathway, thereby increasing KLF2 expression [58]. Woo and colleagues demonstrated that SUMOylation of ERK5 by H2O2 and advanced glycation end products (AGEs), major transducers of diabetic vasculopathy, inhibits shear stress–mediated KLF2 induction in endothelial cells [59]. SUMOylation is a post-translational modification in which small ubiquitin-like modifier (SUMO) proteins are attached to modify target function. They observed that H2O2 and AGEs induce endogenous SUMOylation of ERK5, leading to the reduction of shear stress– induced eNOS expression. SUMOylation of ERK5 downregulates MEF2 and subsequently reduces KLF2 transcriptional activity, thereby suppressing induction of eNOS and the anti-inflammatory response by shear stress [59]. It has been shown that angiopoeitin-1 (Ang-1) also upregulates KLF2 expression through the PI3K/AKT-dependent activation of MEF2 [60].
Progresses and emerging trends of arsenic research in the past 120 years
Published in Critical Reviews in Environmental Science and Technology, 2021
Chengjun Li, Jiahui Wang, Bing Yan, Ai-Jun Miao, Huan Zhong, Wei Zhang, Lena Qiying Ma
At the same time, many studies have explored the genetic basis of how molecularly targeted therapy using ATO could be an effective treatment for APL. Despite the mechanisms being not completely understood, studies in the late 1990s and early 2000s had already shown that ATO could affect the promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR-α) fusion protein and cause differentiation and apoptosis of APL cells (Jing et al., 2001; Tallman, 2001). It has been shown that such phenomena are induced through an ROS-dependent pathway, where ATO increases the cellular content of ROS, especially hydrogen peroxide (H2O2), followed by caspase-3 activation and DNA fragmentation (Woo et al., 2002). Generally, cells possess an efficient antioxidant defense system, mainly composed of enzymes and small molecules of antioxidants such as GSH that can scavenge ROS to maintain relatively stable ROS levels under physiological conditions (Yi et al., 2002); therefore, the GSH content is inversely proportional to the sensitivity of cell lines to ATO and cells with increased ROS levels are more sensitive to ATO (Dai et al., 1999; Yi et al., 2002). Further studies suggested that ATO exerted its therapeutic effect by promoting the degradation of PML and PML-RARa, which was triggered by their SUMOylation (Lallemand-Breitenbach et al., 2008; Lallemand-Breitenbach et al., 2001). Zhang et al. (2010b) demonstrated that arsenic binding induced PML oligomerization, which increased its interaction with the small ubiquitin-like protein modifier (SUMO)–conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation.