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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
Smads are intracellular mediators of TGF-beta that are conserved through evolution. Recent genetic using combinatorial genetics have shown the key roles of Smad2 and Smad4 in gastrulation as well as endoderm formation and liver development.4 Similarly transcription factors Sox 17 (an Sry-related HMG box factor), Mixer (a homeobox protein) and Casanova have been shown to be key determinants of endoderm in Xenopus and zebrafish, with mammalian Sox 17 being crucial for gut endoderm.7 All are expressed in the fetal, adult liver, and other endoderm derived tissues and the fox proteins regulate virtually all liver-specific genes, as well as genes in the lung and the pancreas. 8,9Foxa2 (formerly Hnf3b) is expressed during gastrulation (6.5 days of embryonic gestation in the mouse; E6.5) in the primitive streak (an endoderm progenitor) and in the node (an endoderm and notochord progenitor, Foxa1 (Ηnf3α) expression initiates in the gut endoderm at E7- E8, before organogenesis, whereas Foxa3 (Hnf3c) expression begins in the gut endoderm at E8-E9 but is restricted to the midgut and hindgut regions.10,11 Homozygous mutants for Foxa2 result in embryonic lethality shortly after gastrulation, with defects in the primitive streak, node and notochord that impair neural tube development, and in foregut morphogenesis. 12–15 Homozygous mutation in Foxal leads to impaired pancreatic glucagon expression and consequent postnatal death, whereas homozygous mutation in Foxal appear normal, yet have a decrease in the transcription levels of a number of liver genes. These are seen in Figure 1.
The molecular mechanisms and targeting strategies of transcription factors in cholangiocarcinoma
Published in Expert Opinion on Therapeutic Targets, 2022
Jiao Wang, Fujing Ge, Tao Yuan, Meijia Qian, Fangjie Yan, Bo Yang, Qiaojun He, Hong Zhu
Forkhead box (FOX) proteins are a superfamily of evolutionarily conserved TFs with homologous DNA binding domains of Forkhead (wing-helix), and the FOX superfamily consists of 17 subfamilies named A-S [43]. FOX family members have increasingly played an increasing role in the progression of CCA recently, according to studies. One group initially identifies a candidate tumor-associated antigen, FOXM1, which may be a potential target for immunotherapy against CCA, by analyzing cDNA microarray results of tissues from 25 patients with intrahepatic CCA [44]. Another group discovers that FXOM1 is upregulated significantly in intrahepatic CCA tissues compared with that in peritumoral tissues by immunohistochemical staining analysis of 184 ICC samples [11]. There is a correlation between overexpression of FOXM1 and ICC progression and poor prognoses, and both survivors and disease-free survivors of the FoxM1-high group live about one-third as long as the FOXM1low group [11]. In addition to its correlation with poor prognosis in ICC, FOXM1 protein increases the proliferative, migratory, and invasive capacities of ICC cells in vitro and facilitates ICC progression in vivo as well [11,45]. Activation of FOXM1 by EGF/EGFR and STAT3 under high glucose causes FOXM1 expression to be upregulated, and the EGFR inhibitor Cetuximab strongly inhibits FOXM1 expression by inactivating STAT3 [45]. The combination of Quinoline-based clioquinols and nitroxoline reduces the viability, proliferation, and migration of CCA cells by targeting FOXM1 [46].
WHSC1 promotes wnt/β-catenin signaling in a FoxM1-dependent manner facilitating proliferation, invasion and epithelial-mesenchymal transition in breast cancer
Published in Journal of Receptors and Signal Transduction, 2020
Jinfan Zhang, Jingyu Lu, Yu Chen, Hang Li, Lisheng Lin
FoxM l is a member of the Fox protein family [18]. As a transcriptional regulator, it has a positive effect on cell mitosis and cell cycle [19]. FoxM l is currently considered to be one of the important oncogenic proteins in human tumors [18,20]. FoxM l has an increased expression in a variety of human solid tumors, including liver cancer, breast cancer, colon cancer, prostate cancer and so on [21,22]. Studies have shown that FoxMl could promote cell proliferation and tumor growth by mediating the classical β-catenin/TCF4 signaling pathway in colorectal cancer [23]. In gliomas, FoxMl promotes vascular endothelial growth factor expression and acceleratetumor development [24]. It is reported that FoxM1 regulates EMT, cell proliferation and apoptosis, and the translocation of β-catenin, thereby promoting the genes expression of downstream Wnt/β-catenin [25,26]. However, the specific regulatory mechanism of FoxM1 in BC is still not clear.
When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies
Published in Expert Review of Proteomics, 2018
Julie A. Reisz, Alexander S. Barrett, Travis Nemkov, Kirk C. Hansen, Angelo D’Alessandro
A critical interaction of proteostasis and cancer progression lies in the homeostasis of transcription factors that respond to stresses, alter metabolism, and affect cell lifespan. Modulation of transcription factors such as tumor suppressor p53, HSF-1, forkhead box (Fox) proteins, and Nrf2 through altered expression or mutations can disrupt normal proteostasis and facilitate carcinogenesis [216,217]. For example, levels of Nrf2, which induces the expression of chaperones, proteasome components, and antioxidant enzymes, are increased in many cancers [217,218]. Decreased p53 levels allow for the propagation of malignant cells, and inactivation of p53 by a corrupted chaperone system has been shown to facilitate angiogenesis via vascular endothelial growth factor (VEGF) and NOS [211] (see [219] for a recent review of the interplay between proteostasis and angiogenic factors). Mutations in p53 are many and are well documented to underlie numerous cancers. In a similar manner as for many NDDs, mutations in this protein can lead to aggregation and the formation of nuclear IBs, as has been shown for at least 6 cancer types [220]. Nuclear IBs can activate HSF-1 and also decrease function of the proteasome [220]. Proteasome dynamics is crucial for regulating cellular concentrations of transcription factors, as these proteins are short-lived and degraded by the UPS following activation of DNA promoter regions [221]. Cells have the capacity to turn off or decrease proteolysis under stress conditions to extend the life of transcription factors involved in stress responses; this is manipulated in cancer cells and underlies many of their well-known growth characteristics.