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Nuclear Receptor Coactivators: Mechanism and Therapeutic Targeting in Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Andrew Cannon, Christopher Thompson, Rakesh Bhatia, Sushil Kumar
The function of NCOA2 in HCC is not adequately addressed; however, Suresh and colleagues identified a possible mechanism by which NCOA2 acts to suppress tumor formation [32]. With almost half of all human HCC cases exhibiting overexpression of MYC, the group conducted a Sleeping Beauty-mediated transposon mutagenesis and discovered that loss of NCOA2 with MYC overexpression increased the risk of tumorigenesis [33]. In a mouse model, they reveal that NCOA2 binds the proximal promoters of Vegf, Fgf1, and Masp1, with expression of all three upregulated in shNCOA2 KD. Conversely, NCOA2 KD decreased the expression of Shp, Dkk4, and Cadm4 in HCC cell line, Huh7. The KD of these three genes increased proliferation and tumor volume from orthotopic implantation. Overexpression of Shp, Dkk4, Cadm4, and Thrsp decreased cell proliferation and tumor volume, but only Shp and Cadm4 demonstrated reductions of orthotopic tumor burden in the setting of NCOA2 KD. These data together suggest a plausible mechanism by which NCOA2 acts with nuclear partners to repress liver tumorigenesis.
Complement-Mediated Lipopolysaccharide Release
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Several investigators noted that the human mannose-binding protein (MBP) and lung surfactant proteins are structurally similar to the C1q molecule (reviewed in Ref. 18). This led to the speculation that proteins other than C1q may participate in complement activation. Human MBP directly binds to the C1 complex serine proteases C1r and C1s and can mediate activation of the classical pathway of complement. However, when isolated from serum, MBP is usually associated with a 100 kDa serine protease. This dimeric complex was originally designated Ra-reactive factor because it was shown to specifically bind rough LPS of the Ra chemotype (19). The MBP-associated serine protease (MASP) (1) shares approximately 39% amino acid homology with human C1r and C1s, (2) contains a histidine loop structure, which is highly conserved among serine proteases, and (3) can cleave C4 and C2, or may directly bind to and hydrolyze C3, to produce functional classical and alternative pathway C3 convertases (18). Thus, the MBP-MASP complex may bind TV-acetylglucosamine-, 7V-acetylmannosamine-, and mannose-containing lipopolysaccharides synthesized by E. coliand Salmonella spp. and directly activate the classical and alternative pathways of complement in an antibody- and C1q-independent manner.
The complement system in health and disease
Published in Gabriel Virella, Medical Immunology, 2019
The lectin pathway is initiated by target recognition through the binding of circulating lectins, such as plasma mannan-binding lectin (MBL) and Ficolins 1–3. These protein components belong to the collectin family, structurally resemble C1q, and are involved with the recognition of foreign organisms such as bacteria and virus. Mannan, a constituent of the polysaccharide capsules of many pathogenic fungi and yeasts (e.g., Cryptococcus neoformans and Candida albicans), is one of several polysaccharide substances to which MBL binds via Ca2+-dependent interactions, while bacterial lipoteichoic acid and peptidoglycan associate with serum Ficolins. In addition to carbohydrate motifs of microorganisms, MBL can bind to glycoproteins on the envelope of several types of viruses. The activation of the lectin pathway does not involve antigen-antibody interactions. Like the alternative complement pathway, the lectin pathway is an innate system designed to activate the complement system independently of specific antibodies, and as such requires no adaptive immune system help. Both mannan-binding lectin and ficolins are acute-phase reactants, meaning that their concentration increases during infection and inflammation. Both types of lectins stay associated with serum serine proteases, and upon binding initiation proceeds through the activations of processes mediated by MBL-associated serine proteases (MASPs) such as MASP-1, MASP-2, and MASP-3. These proteases form a tetrameric complex similar to the one formed by C1r and C1s of the classical pathway, and MASP-2 subsequently cleaves C4 and C2, and then subsequently C3 in the same manner as that of the classical pathway (Figure 9.3).
Activation of Complement System in Henoch-Schönlein Purpura Nephritis
Published in Fetal and Pediatric Pathology, 2022
Hea Min Jang, Heesun Baek, Man Hoon Han, Yong Jin Kim, Chan-Duck Kim, Yong-Lim Kim, Sun-Hee Park, Min Hyun Cho
Another study demonstrated that complement pathway activity was also involved in the pathophysiology of HSPN via a similar pathophysiological mechanism as seen with IgAN. In their meta-analysis, Chan et al. found C3 reduction to be associated with renal manifestations in HSP [10]. Davin et al. reported that mannose-binding protein C, MASP-1, and C4d associated with the lectin pathway were observed in biopsies of 50% of patients, but C1q deposition was not observed. Their study revealed that the lectin pathway is associated with renal disease progression in HSPN [1]. Endo et al. also identified glomerular deposition of components associated with lectin pathways, such as MBL, MASP-1 and C4 binding proteins in the renal biopsies of HSPN patients. Based on these reports, it has been suggested that the lectin pathway of complement is one of the major pathogenetic mechanisms underlying HSPN, similar to IgAN [5]. In this study, the C4d positivity rate was 57.1% in 35 children and 41.7% in 12 adults with HSPN. Among the pediatric patients, 68% who were less than 10 years of age and 30% who were between 10 and 18 years of age were C4d-positive, respectively. When three age groups (0-10 years, 10-18 years, and ≥18 years) were considered, the C4d positivity rate was significantly higher among younger patients, a finding that was similar to what we previously reported about C4d deposition in pediatric IgAN [7].
Acute post-streptococcal glomerulonephritis: analysis of the pathogenesis
Published in International Reviews of Immunology, 2021
Jesús Mosquera, Adriana Pedreañez
Both classical and alternative pathways of complement activation can occur during the course of APSGN [18]. In this regard, the classical complement pathway is frequently activated in patients with early APSGN [19], suggesting the interaction of streptococcal antigens with their antibodies. In addition, streptococcal protein H attached to Fc region of IgG may activate the classic pathway [20]. A role of streptococcal protein H in the pathogenesis of APSGN has been reported [21]. A third complement activation pathway, termed the “lectin pathway” (LP) had been described [22]. LP is identical to the classical pathway except for the initiation of the complement cascade. Instead of a C1q/C1 complex the LP initiation is done by an opsonin named mannose-binding lectin (MBL). This lectin binds to mannose residues on the pathogen surface which in turn activates the associated serine proteases MASP1 and MASP2 [23]. The LP activation in APSGN is controversial, it has been reported LP activation in this disease [24], but others reports failed to find evidence of this activation [21].
Revisiting the complement system in systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2020
Madhubala Sharma, Pandiarajan Vignesh, Karalanglin Tiewsoh, Amit Rawat
C2 defect is considered to be the commonest complement deficiency, with an incidence of 1 in 20,000 among Caucasians [46]. Complement C2 gene is positioned on the short(p) arm of chromosome 6, in HLA class III region [47]. Activated C1 cleaves C2 into C2b and C2a. C3 convertase is formed by C2a serine protease. C2 also has a vital role in the lectin pathway [48,49]. Ficolins or mannose-binding lectin (MBL) along with Mannan-binding lectin serine protease-1 (MASP-1) binds to carbohydrate moieties to activate MASP-2, it then splits C2 along with C4 to form C3 convertase, like in the classical pathway[50].