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Familial Acute Myeloid Leukemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CCAAT/enhancer binding protein (C/EBP), alpha gene (CEBPA) is a single exon gene located on chromosome 19q13.1 band. The gene belongs to a family of basic leucine zipper proteins, and encodes for a transcription factor that is crucial for maturation of hematopoietic myeloid cells; no mature granulocytes are observed in CEBPA-mutant mice and the t(8;21) translocation downregulates CEBPA to lead to AML [35–37]. The CEBPA gene has 2 transactivation domains at the N-terminus, and a basic region and leucine zipper region at the C-terminus. Mutations in CEBPA may be present in sporadic AML in 5%–14% cases. Most commonly, mutations in the N-terminus cause a frameshift, leading to premature termination and absence of the normal, full-length 42 kDa protein, but still allowing downstream expression for formation of the smaller 30 kDa protein, a dominant-negative isoform. Mutations in the C-terminus disrupt the leucine zipper region, which prevents dimerization and loss of DNA activity [36].
Mouse Knockout Models of Biliary Epithelial Cell Formation and Disease
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Hepatocytes undergo a transition from a hepatic endodermal epithelum to a nonpolarized cellidar phenotype (hepatoblasts) and then back to a fully differentiated epithelium. By E17, hepatocytes have developed their characteristic cuboidal cell morphology and, are ready to undergo the transition from a hemopoietic support role to primary cells controlling metabolite and serum protein levels. During this perinatal phase, the hepatocytes begin to express many new genes under the control of the transcription factor C/EBPbeta. (CCAAT/enhancer binding protein. They also form the cell junctions that are required to create a polarized epithelium, with the apical cell surface being the site of bile secretion and the basal cell surface opposed to the endothelial cells.
Increasing the Sensitivity of Adipocytes and Skeletal Muscle Cells to Insulin
Published in Christophe Wiart, Medicinal Plants in Asia for Metabolic Syndrome, 2017
Ethanol extract of Dioscorea opposita L. given orally to Sprague–Dawley rats at a dose of 300 mg/kg/day for 2 weeks prevented insulin resistance induced by subcutaneous injection of dexamethasone as evidenced by a decrease of plasma glucose from 9.5 to 2.8 mM (normal: 4.5 mM) and insulinemia from 0.7 to 0.2 nM (normal: 0.09 nM), respectivley.338 The extract lowered 30 minutes peak glycemia in oral glucose tolerance test.338 The extract at a concentration of 50 μg/mL increased insulin-mediated glucose uptake by 3T3-L1 adipocytes by 5 folds together with increased expression of glucose transporter-4.338 (4E,6E)-1,7-bis(4-hydroxyphenyl)-4, 6-heptadien-3-one, (3R,5R)-3,5-dihydroxy-1,7-bis(4-hydroxyphenyl)-3,5-heptanediol, batatasin I, (1E,4E,6E)-1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one isolated from the rhizomes of Dioscorea oppositifolia L. at a concentration of 20 μM inhibited the accumulation of triglycerides in dexamethasone-insulin-3-isobutyl-1-methylxanthine-induced differentiating 3T3-L1 preadipocytes concurrent decreased expression of peroxisome proliferator-activated receptor-γ.339 Batatasin I and (1E,4E,6E)-1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one down-regulated the expression of CCAAT/enhancer-binding protein-α.338 (4E,6E)-1,7-bis(4-hydroxyphenyl)-4,6-heptadien-3-one and batatasin I induced the phosphorylation of adenosine monophosphate-activated protein kinase.338 Batasin I boosted the expression of carnitine palmitoyltransferase-1.338
CEBPA mutants down-regulate AML cell susceptibility to NK-mediated lysis by disruption of the expression of NKG2D ligands, which can be restored by LSD1 inhibition
Published in OncoImmunology, 2022
Meng Liu, Mengbao Du, Jian Yu, Zijun Qian, Yang Gao, Wenjue Pan, Xiujie Zhao, Mowang Wang, Huimin Li, Jiaqi Zheng, Qianshuo Huang, Li-Mengmeng Wang, Haowen Xiao
CCAAT/enhancer-binding protein α (C/EBPα) is one of the most studied lineage-specific transcription factors (TFs) in hematopoiesis, which is mainly involved in cell fate decisions, including a key role in governing myeloid differentiation.1 In line with the critical role of C/EBPα in granulocytic differentiation, the CEBPA gene was found to be mutated in approximately 7% of all patients with acute myeloid leukemia (AML), and the incidence increased to 10–15% in AML patients with normal karyotype.2 Full-length C/EBPα is a 42-kDa protein (C/EBPα-p42) that contains two transactivation domains (TAD, TAD1 and TAD2) in the amino terminus and a basic leucine zipper domain (bZIP) at its carboxy terminus for DNA binding. Two major categories of collaborating CEBPA mutations have been described in human AML: (1) frameshift (FS) insertions or deletions affecting the N-terminal region resulting in a loss of the 42-kDa protein and overexpression of a shorter 30-kDa isoform (C/EBPα-p30), proposed to exhibit a dominant negative activity, and (2) in-frame mutations in the C-terminal region that alter the basic leucine zipper domain, leading to impaired DNA binding and disrupted protein–protein interactions.3 Furthermore, it has been shown that nearly 10% of AMLs with biallelic mutations in CEBPA also harbor a germline CEBPA mutation.4 These germline mutations are commonly additional C-terminal CEBPA mutations.5,6 So CEBPA mutations may be clustered to germline mutations, N-terminal frameshift mutations and C-terminal mutations.
Low Transthyretin Levels Predict Poor Prognosis in Cancer Patients in Palliative Care Settings
Published in Nutrition and Cancer, 2018
Tomofumi Miura, Koji Amano, Akemi Shirado, Mika Baba, Taketoshi Ozawa, Nobuhisa Nakajima, Akihiko Suga, Yoshihisa Matsumoto, Mie Shimizu, Satofumi Shimoyama, Toshiyuki Kuriyama, Yoshinobu Matsuda, Tomoyuki Iwashita, Ichiro Mori, Hiroya Kinoshita
TTR levels are influenced by inflammation (20). Therefore, this study analyzed GPS, an indicator of systemic inflammation as well as TTR levels. The GPS scores of 2 in more than half of the subjects indicated systemic inflammation. Several mechanisms associated with low TTR levels have been documented (21). Most TTR is produced in the liver (22). A correlation exists between hepatic protein synthesis and free amino acid concentration in hepatocytes (23). A decrease in amino acid intake, such as tryptophan or leucine, may suppress protein synthesis in the liver (24–26). The binding of hepatic nuclear factors (HNF) to CCAAT/enhancer binding proteins (C/EBP) enhances the transcription of the TTR gene (2). The binding of HNF-4α, a crucial mediator among HNFs, to the TTR promoter was significantly reduced in a cytokine-induced acute phase response (3). In fact, present study showed that TTR had moderately correlated with CRP levels. Therefore, this study showed that decreased TTR levels may be a sensitive indicator that reflects critically severe conditions since both malnutrition and an inflammatory state may decrease TTR levels in cancer patients in palliative care settings.
Development of gamma-tocotrienol as a radiation medical countermeasure for the acute radiation syndrome: current status and future perspectives
Published in Expert Opinion on Investigational Drugs, 2023
The role of CCAAT enhancer binding protein delta (CEBPD) has been investigated for its role in radioprotective efficacy of GT3 [59]. Using CEBPD−/− and CEBPD+/+ (C57BL/6 background) mice, a study has been conducted to identify a novel role for CEBPD in GT3-mediated protection against radiation-induced injury. In brief, CEBPD was identified to participate in radioprotection of GT3 via modulating radiation-induced oxidative and nitrosative stress. The exact mechanism of CEBPD upregulation by GT3 and irradiation remains unclear [59].