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Colon cancer: pathology and natural history
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
APC protein interacts with leukocyte enhancing factor (LEF-1) and members of the T-cell factor (Tcf) family of transcription factors17. It has been reported that LEF-1 binds directly to ß-catenin and translocates the latter to the nucleus, thus potentially mediating its role in the Wnt-1 signalling pathway. Constitutive complexing of ß-catenin with Tcf-4 and LEF-1 has been reported in colorectal carcinoma cell lines homozygous for the deletion of APC17, and is believed to be related to cancer progression through persistent activation of downstream target genes which are uncharacterized.
Pathogenesis: Molecular mechanisms of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Anastasia E. Markatseli, Theodora E. Markatseli, Alexandros A. Drosos
Lef/Tcf transcription factors: Various isoforms of Lef/Tcf transcription factors have been described in the literature. The main isoforms expressed in osteoblasts are Tcf1 and Tcf4 (17,23). In the absence of Wnt signaling, Lef/Tcf factors are bound to transcriptional co-repressors (266–268). The activation of the canonical Wnt signaling pathway leads to the replacement of co-repressors by β-catenin and its binding to Lef/Tcf factors. Of note, several studies indicate that the activity of Lef/Tcf transcription factors is increased in areas of the skeleton that undergo bone remodeling (248,269–272).
DMARD Treatment in Patients with Psoriatic Arthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Rafael Valle Oñate, Andrea Chaparro
There are no data on the effect of LEF on enthesitis, spondylitis, or radiographic progression. Available data suggest that in PsA, LEF has a moderate symptom-modifying effect on peripheral synovitis and might improve dactylitis. Its effects on the other articular manifestations of psoriatic disease are unknown [26].
Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management
Published in Drug Delivery, 2022
Mariam Zewail, Passent M. E. Gaafar, Mai M. Ali, Haidy Abbas
Leflunomide (LEF) is an isoxazole derivative prodrug that was first approved for rheumatoid arthritis treatment at 1998. It showed promising results for its application as an anti-tumor agent. Upon administration, LEF is completely metabolized to its active metabolite teriflunomide (A771726) (Zhang & Chu, 2018). The prodrug activation was even confirmed in the skin upon topical administration (Bae & Park, 2016). LEF exerts its pharmacological anti-tumor effects by several mechanisms. It can act by inhibiting the de novo pyrimidine biosynthesis through suppression of mitochondrial dihydroorotatedehydrogenase (DHODH) enzyme which plays a vital role in cancer cells apoptosis through suppression of B and T cells (Sanders & Harisdangkul, 2002; Keen et al., 2013; Zhang & Chu, 2018; Zewail, 2021). Also, LEF can act as a tyrosine kinase inhibitor and was used for the treatment of several types of tumors (Pytel, Sliwinski et al., 2009). In addition, LEF showed selective inhibition of platelet-derived growth factor (PDGF) mediated phosphorylation. Signals through PDGF stimulate numerous functions such as cell growth, proliferation, and differentiation (Zhang & Chu, 2018). Furthermore, LEF can act as aryl hydrocarbon receptor (AhR) agonist by stimulating AhR which can inhibit cancer cells’ proliferation and act as a tumor suppressor in cancer animal models (O’Donnell et al., 2010). Furthermore, it was reported that LEF can inhibit stemness of cancer stem cells (White et al., 2011).
Lef1 is transcriptionally activated by Klf4 and suppresses hyperoxia-induced alveolar epithelial cell injury
Published in Experimental Lung Research, 2022
Min Yang, Xueshan Huang, Fang Shen, Juanjuan Yi, Yanni Meng, Yanping Chen
Lef1 is a transcription factor that is known to be involved in canonical Wnt signaling and to regulate cell proliferation during lung development.34Lef1 is found to be abundantly expressed in the alveolar epithelium and mesenchyme adjacent to the lung epithelium.35 By recruiting to the promoter of vascular endothelial growth factor (Vegf), Lef1 elevates expression of Vegf and promotes epithelial and endothelial cell proliferation.36 Additionally, LEF1 may interact directly with the miR-124 promoter region to influence the maturation of embryonic pulmonary epithelial cells.37 To elucidate the regulatory mechanism underlying BPD, this work focused on LEF1/Lef1 and discovered that LEF1/Lef1 expression was diminished in clinical BPD serum samples and hyperoxia-induced MLE-12 cells. Additionally, we discovered that overexpression of Lef1 might protect AECs from hyperoxia-induced damage.
Interaction between CASP8AP2 and ZEB2-CtBP2 Regulates the Expression of LEF1
Published in Pediatric Hematology and Oncology, 2022
Chan-Juan Wang, Ming-Zhu Jia, Li-Ping Deng, Wei-Jing Li, Qing Zhang, Tong-Jia Zhang, Shu-Yan Li, Lei Cui, Zhi-Gang Li
LEF1 is a critical transcription factor in the Wnt signaling pathway and plays a vital regulatory role in the maintenance, proliferation, and differentiation of hematopoietic stem/progenitor cells.23,24 It also plays an essential role in leukemia, and its high expression is related to the recurrence of ALL.16 As mentioned above, our study confirmed that CASP8AP2 and CtBP2 bind to the ZEB2 binding site in the LEF1 promoter region at position −117 through the interaction with ZEB2 and inhibit the transcription and expression of LEF1. Moreover, CASP8AP2 affected the binding of ZEB2 and the LEF1 promoter, and the interaction between CtBP2 and ZEB2 and LEF1 expression was upregulated after CASP8AP2 was knocked down. Therefore, by interacting with CtBP2 and ZEB2 to regulate LEF1 expression, thereby affecting the stemness of leukemia cells, CASP8AP2 may be one of the important factors that affect drug resistance of ALL cells and clinical prognosis.