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Hereditary primary hyperparathyroidism and multiple endocrine neoplasia
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
The MEN1 protein menin is predominantly found in the nucleus and is involved in multiple cellular processes that regulate cell division, apoptosis, gene transcription, response to DNA damage and DNA replication, and repair in a cell type–dependent manner.36 Menin binds to several transcription factors and can repress or enhance their effects. The same pocket in menin binds to JunD (a transcription factor) and to MLL (part of a histone methyltransferase complex). Menin represses the transcriptional activity of JunD, while stimulating the activity of MLL, which in both cases leads to decreased cell proliferation.37 It can also regulate hormone secretion/production, including that of gastrin (via JunD), PTH (via Smad3), and prolactin (via transforming growth factor-β). It binds nuclear factor-κB (NF-κB) as well as nuclear receptors and controls the subcellular localization of β-catenin. Menin increases the expression of cyclin-dependent kinase inhibitors, including CDKN1A, CDKN1B, CDKN2B, and CDKN2C in many different ways, including histone methylation and especially in response to DNA damage.38 These cyclin-dependent kinase (CDK) inhibitors prevent progression through the cell cycle, and mutations in these genes are a rare cause of MEN1-like syndromes (see above).35 In mice, knockout of one copy of the MEN1 gene gives rise to a similar spectrum of endocrine tumors.39
Multiple endocrine neoplasia type 1
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Using yeast two-hybrid systems, an interacting protein of menin has been isolated which turns out to be the API transcription factor JUND (Agarwal et al., 1999). The API transcription factors have basic leucine zipper (bZip) domains that pair to bind DNA as a Y-shaped heterodimer. Menin has been found to specifically bind to JUND via its N-terminal, but not to the other members of JUN or FOS. Menin causes repression on JUND-activated transcription and one recent study has shown that this repression is released by the histone deacetylase inhibitor trichostatin A, suggesting that the repression is dependent on histone deacetylation (Gobl et al., 1999). Some, but not all, MEN1 mutations disrupt its binding to JUND causing an increase in JUND-activated transcription. Based on the binding effects demonstrated by MEN1 mutations from different locations, three binding domains have been identified: amino acids 1–40, 139–242 and 323–428 (Figure 1)and there are a number of disease-causing mutations that are located outside the binding domains. The identification of other interacting proteins, which may constitute parts of the menin-JUND complex or separate functional entities, may further elucidate the molecular mechanisms involved in MEN1 tumorigenesis.
Proto-Oncogene and Onco-Suppressor Gene Expression
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The c-jun-like genes jun-B and jun-D are functionally important members of the jun gene family.234-236 These two genes were first identified by screening of cDNA libraries prepared from serum-stimulated NIH/3T3 cells. The tissue distribution and levels of expression of the members of the jun family may be different. Whereas jun-B behaves like c-jun in relation to its high inducibility by serum and may be considered as an immediate-early gene in the mitogenic response, jun-D is already expressed in serum-starved mouse fibroblasts and is not stimulated by the addition of serum. Both c-jun and jun-B are developmentally regulated in the immature and mature mouse testis.237 Expression of the c-jun and jun-B genes is increased after dissociation of spermatogenic cells, with maximal induction in prepuberal animals. Differential expression of the genes c-jun and jun-B is observed in some types of cells, for example, in TGF-α-stimulated BC3H1 muscle cells.238 The physiological activities of c-Jun and Jun-B have been found to differ in several aspects, such as in their ability to activate AP-1 responsive genes.239 In general, Jun-B is much less active than c-Jun for its gene trans-activation and cellular transformation abilities, and these differences depend on only a few amino acid differences within the conserved DNA-binding domain of the two proteins.240 In some systems, the Jun-B protein may function as a negative regulator of c-jun gene expression.
Selective inhibitors for JNK signalling: a potential targeted therapy in cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Qinghua Wu, Wenda Wu, Vesna Jacevic, Tanos C. C. Franca, Xu Wang, Kamil Kuca
JNK1 acts synergistically with Bcl-2 to promote prolonged cell survival in the absence of IL-3 or in response to different stresses58. The anticancer drug bortezomib activates JNK signalling leading to Bcl-2 phosphorylation and autophagy47. JNK and autophagy activation play a pro-survival role in this context and their inhibition increases the cytotoxic effects of bortezomib in PEL cells. JNK-mediated survival signalling also involves the transcription factor JunD59, as the JNK/JunD pathway collaborates with NF-κB to upregulate the expression of the antiapoptotic gene cIAP-2. In the absence of activated NF-κB, the JNK pathway promotes an apoptotic response60.
Biological Markers of Oxidative Stress in Cardiovascular Diseases: After so Many Studies, What do We Know?
Published in Immunological Investigations, 2018
Josef Fontana, Michal Zima, Vaclav Vetvicka
A novel alternative is the use of targets such as activator protein-1 transcription factor JunD, SIRT-1, or mitochondrial adaptor p66Shc. These molecules are involved in controlling ROS production, either by attenuating oxidative stress or affecting apoptosis. Another possibility is to affect endoplasmic reticulum, where a C.EBO homologous protein CHOP plays a central proapoptic role in stressed reticulum (Tsukano et al., 2010).
Regulation of T cell differentiation by the AP-1 transcription factor JunB
Published in Immunological Medicine, 2021
Takaharu Katagiri, Hideto Kameda, Hiroyasu Nakano, Soh Yamazaki
The Jun family has three members, c-Jun, JunB, and JunD [35]. Although these proteins have similar amino acid sequences, they are known to exert different functions [36]. For instance, JunD-deficient mice are viable, whereas c-Jun-deficient mice have abnormal liver and heart and die at embryonic day 12.5 [37]. Mice with systemic Junb deficiency die in utero owing to placental hypoplasia on embryonic day 8 [3]. The BATF-Jun heterodimer was considered as a negative regulator of AP-1 because it targets the transactivation domain of Jun [38]. However, subsequent analyses indicated that the BATF-Jun heterodimer exhibits positive transcriptional activity and may partially suppress AP-1 function [31,38]. We have previously provided the genetic evidence that JunB is essential for Th17 cell differentiation [7]. JunB forms dimeric AP-1 with BATF and induces the expression of Th17 cell-related genes [7–9]. Junb-deficient CD4+ T cells fail to differentiate into Th17 cells, and Junb-deficient mice are resistant to EAE induction [7,8]. In addition, the adoptive transfer of CD4+ CD45RBhigh T cells from wild-type mice to syngeneic recipients lacking T and B cells, such as Rag1 or Rag2-deficient mice, was shown to induce colitis [11]; however, the transfer of these cells from Junb-deficient mice with T cells does not induce colitis in recipients because of the loss of pathogenic Th17 cells [9]. In recent years, a heterodimer of the AP-1 transcription factor was shown to form a trimer with interferon regulatory factor 4 (IRF4) or IRF8 and regulate gene expression [39]. Furthermore, it was found to be important for the differentiation of Th17 cells and cytotoxic T cells [40,41]. Other groups reported that JunB promotes the binding of IRF4 and BATF to the region near the Rorc gene [8,9]. JunB is also thought to suppress the expression of Foxp3, a transcription factor known to inhibit Th17 cell differentiation by antagonizing RORγt function [42]. This is because Foxp3 expression is elevated in Junb-deficient cells under Th17 polarization conditions [7]. This increase is also observed in T cells that lack the JunB partner BATF [33]. These results indicate that JunB regulates the expression of Th17-related factors in cooperation with BATF (Figure 1(A)).