We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix-loop-helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons' fate into "hair cells", highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of "intraganglionic" HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.
- MeSH
- Cochlea cytology metabolism MeSH
- Humans MeSH
- Neurogenesis genetics physiology MeSH
- Basic Helix-Loop-Helix Transcription Factors genetics metabolism MeSH
- Transcription Factors genetics metabolism MeSH
- Hair Cells, Auditory metabolism MeSH
- Gene Expression Regulation, Developmental MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Brassinosteroids (BRs) are essential phytohormones regulating various developmental and physiological processes during normal growth and development.cog1-3D(cogwheel1-3D) was identified as an activation-tagged genetic modifier ofbri1-5, an intermediate BR receptor mutant in Arabidopsis (Arabidopsis thaliana).COG1encodes a Dof-type transcription factor found previously to act as a negative regulator of the phytochrome signaling pathway.cog1-3Dsingle mutants show an elongated hypocotyl phenotype under light conditions. A loss-of-function mutant or inducible expression of a dominant negative form ofCOG1in the wild type results in an opposite phenotype. A BR profile assay indicated that BR levels are elevated incog1-3Dseedlings. Quantitative reverse transcription-polymerase chain reaction analyses showed that several key BR biosynthetic genes are significantly up-regulated incog1-3Dcompared with those of the wild type. Two basic helix-loop-helix transcription factors,PIF4andPIF5, were found to be transcriptionally up-regulated incog1-3DGenetic analysis indicated that PIF4 and PIF5 were required for COG1 to promote BR biosynthesis and hypocotyl elongation. Chromatin immunoprecipitation and electrophoretic mobility shift assays indicated that COG1 binds to the promoter regions ofPIF4andPIF5, and PIF4 and PIF5 bind to the promoter regions of key BR biosynthetic genes, such asDWF4andBR6ox2, to directly promote their expression. These results demonstrated that COG1 regulates BR biosynthesis via up-regulating the transcription ofPIF4andPIF5.
- MeSH
- Arabidopsis genetics metabolism MeSH
- Models, Biological MeSH
- Biosynthetic Pathways genetics MeSH
- Point Mutation genetics MeSH
- Brassinosteroids biosynthesis MeSH
- Ethyl Methanesulfonate MeSH
- Phenotype MeSH
- Hypocotyl growth & development metabolism MeSH
- Promoter Regions, Genetic genetics MeSH
- Arabidopsis Proteins genetics metabolism MeSH
- Gene Expression Regulation, Plant MeSH
- Genes, Plant MeSH
- Base Sequence MeSH
- Suppression, Genetic MeSH
- Basic Helix-Loop-Helix Transcription Factors genetics metabolism MeSH
- Transcription Factors genetics metabolism MeSH
- Up-Regulation genetics MeSH
- Protein Binding genetics MeSH
- Publication type
- Journal Article MeSH
UNLABELLED: Backround. There is increasing evidence of the role of hypoxia or pseudohypoxia in tumorigenesis, including pheochromocytoma (PHEO) and paraganglioma (PGL). (Pseudo)hypoxia leads to activation of hypoxia-inducible transcription factors (HIFs) and thus, promotes the transcription of hypoxia-responsive genes which are involved in tumorigenesis. Recently identified is a new syndrome consisting of multiple and recurrent PGLs or PHEOs, somatostatinoma, and congenital polycythemia, due to somatic hypoxia-inducible factor 2α gene (HIF2A) mutations. METHODS AND RESULTS: PubMed and Web of Science online databases were used to search reviews and original articles on the HIF, PHEO/PGL, and Pacak-Zhuang syndrome. CONCLUSIONS: The novel somatic and germline gain-of-function HIF2A mutations described latterly emphasize the role of the HIF-2α in the PHEO/PGL development and these findings designate HIF, especially HIF-2α, as a promising treatment target.
- MeSH
- Carcinogenesis genetics MeSH
- Humans MeSH
- Mutation MeSH
- Paraganglioma drug therapy genetics MeSH
- Polycythemia congenital drug therapy genetics MeSH
- Somatostatinoma drug therapy genetics MeSH
- Syndrome MeSH
- Basic Helix-Loop-Helix Transcription Factors genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- MeSH
- Humans MeSH
- Mutation MeSH
- Duodenal Neoplasms genetics metabolism pathology MeSH
- Paraganglioma genetics metabolism pathology MeSH
- Basic Helix-Loop-Helix Transcription Factors genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Letter MeSH
- Research Support, N.I.H., Intramural MeSH
Juvenile hormone (JH) signaling is realized at the gene regulatory level by receptors of the bHLH-PAS transcription factor family. The sesquiterpenoid hormones and their synthetic mimics are agonist ligands of a unique JH receptor (JHR) protein, methoprene-tolerant (MET). Upon binding an agonist to its PAS-B cavity, MET dissociates from a cytoplasmic chaperone complex including HSP83 and concomitantly switches to a bHLH-PAS partner taiman, forming a nuclear, transcriptionally active JHR heterodimer. This course of events resembles the vertebrate aryl hydrocarbon receptor (AHR), activated by a plethora of endogenous and synthetic compounds. Like in AHR, the pliable PAS-B cavity of MET adjusts to diverse ligands and binds them through similar mechanisms. Despite recent progress, we only begin to discern agonist-induced conformational shifts within the PAS-B domain, with the ultimate goal of understanding how these localized changes stimulate the assembly of the active JHR complex and, thus, fully grasp the mechanism of JHR signaling.
- MeSH
- Juvenile Hormones * metabolism MeSH
- Signal Transduction MeSH
- Basic Helix-Loop-Helix Transcription Factors metabolism genetics chemistry MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The sesquiterpenoid juvenile hormone (JH) is vital to insect development and reproduction. Intracellular JH receptors have recently been established as basic helix-loop-helix transcription factor (bHLH)/PAS proteins in Drosophila melanogaster known as germ cell-expressed (Gce) and its duplicate paralog, methoprene-tolerant (Met). Upon binding JH, Gce/Met activates its target genes. Insects possess multiple native JH homologs whose molecular activities remain unexplored, and diverse synthetic compounds including insecticides exert JH-like effects. How the JH receptor recognizes its ligands is unknown. To determine which structural features define an active JH receptor agonist, we tested several native JHs and their nonnative geometric and optical isomers for the ability to bind the Drosophila JH receptor Gce, to induce Gce-dependent transcription, and to affect the development of the fly. Our results revealed high ligand stereoselectivity of the receptor. The geometry of the JH skeleton, dictated by two stereogenic double bonds, was the most critical feature followed by the presence of an epoxide moiety at a terminal position. The optical isomerism at carbon C11 proved less important even though Gce preferentially bound a natural JH enantiomer. The results of receptor-ligand-binding and cell-based gene activation assays tightly correlated with the ability of different geometric JH isomers to induce gene expression and morphogenetic effects in the developing insects. Molecular modeling supported the requirement for the proper double-bond geometry of JH, which appears to be its major selective mechanism. The strict stereoselectivity of Gce toward the natural hormone contrasts with the high potency of synthetic Gce agonists of disparate chemistries.
- MeSH
- Drosophila melanogaster chemistry genetics metabolism MeSH
- Juvenile Hormones chemistry metabolism MeSH
- Models, Molecular MeSH
- Drosophila Proteins metabolism MeSH
- Receptors, Cell Surface metabolism MeSH
- Stereoisomerism MeSH
- Basic Helix-Loop-Helix Transcription Factors metabolism MeSH
- Transcription Factors metabolism MeSH
- Protein Binding MeSH
- Gene Expression Regulation, Developmental MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
In the present study, we investigated protein expression of the transcription factors mammalian doublesex and mab-3 related transcription factor 1 (DMRT1), basic helix-loop-helix transcription factor-like 5 (TCLF5), and octamer-binding transcription factor 4 (OCT4) in normal human spermatogenesis, testicular mixed germ cell-sex cord stromal tumor (MGC-SCST), spermatocytic tumor, and seminoma. In normal human spermatogenesis, DMRT1 is expressed in the nuclei of spermatogonia but not in those of more mature germ cells. By way of contrast, TCLF5 is expressed in the nuclei of some clusters of primary spermatocytes that have entered meiosis 1, in secondary spermatocytes, and in round (early) spermatids in the seminiferous tubules of adults during the reproductive years. OCT4 is expressed in primordial germ cells but not in the seminiferous tubules of the normal adult testis during the reproductive years. DMRT1 is expressed in the germ cells of both testicular MGC-SCST and spermatocytic tumor, whereas TCLF5 is not expressed in either neoplasm. These low-grade neoplasms, however, differ histologically in that all the germ cell nuclei of testicular MGC-SCST resemble spermatogonia, whereas in spermatocytic tumor, the nuclei of the medium-sized and large cells resemble those of primary spermatocytes. Both neoplasms lack expression of OCT4. By way of contrast, in seminoma, a fully malignant testicular germ cell tumor, the germ cell nuclei express OCT4 but do not express either DMRT1 or TCLF5.
- MeSH
- Biopsy MeSH
- Cell Nucleus chemistry pathology MeSH
- Neoplasms, Germ Cell and Embryonal chemistry pathology MeSH
- Immunohistochemistry MeSH
- Humans MeSH
- Biomarkers, Tumor analysis MeSH
- Octamer Transcription Factor-3 analysis MeSH
- Seminiferous Tubules chemistry pathology MeSH
- Seminoma chemistry pathology MeSH
- Spermatocytes chemistry pathology MeSH
- Spermatogenesis MeSH
- Testicular Neoplasms chemistry pathology MeSH
- Basic Helix-Loop-Helix Transcription Factors analysis MeSH
- Transcription Factors analysis MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which plays numerous and pivotal roles in human physiology and pathophysiology. Therefore, pharmacotherapeutic targeting of the AhR is a highly pertinent issue. The identification of new AhR ligands and the characterization of the interactions between the AhR ligands and AhR protein requires appropriate methodology. In spite the AhR is monomeric intracellular soluble receptor, the full-length human AhR protein has not been crystallized so far, and its isolation in a form applicable in the binding assays is highly challenging. Recent advances, including crystallization of AhR fragments, recombinant protein technologies, and cryogenic electron microscopy, allowed for exploitation of diverse experimental techniques for studying interactions between ligands and the AhR. In the current paper, we review existing AhR ligand binding assays, including their description, applicability and limitations.
The aim of this paper was to summarise knowledge of IL-22 involvement in multiple sclerosis (MS) and the possible link between IL-22 and two transcription factors - AHR and c-Maf. The conclusion is that despite numerous studies, the exact role of IL-22 in the pathogenesis of MS is still unknown. The expression and function of c-Maf in MS have not been studied. It seems that the functions of c-Maf and AHR are at least partly connected with IL-22, as both directly or indirectly influence the regulation of IL-22 expression. This possible connection has never been studied in MS.
- MeSH
- Adaptor Proteins, Signal Transducing physiology MeSH
- Interleukins physiology MeSH
- Humans MeSH
- Receptors, Aryl Hydrocarbon physiology MeSH
- Multiple Sclerosis etiology MeSH
- Basic Helix-Loop-Helix Transcription Factors physiology MeSH
- Transcription Factors physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
- MeSH
- Humans MeSH
- Small Cell Lung Carcinoma * genetics metabolism surgery MeSH
- Cell Line, Tumor MeSH
- Lung Neoplasms * genetics metabolism surgery MeSH
- Prognosis MeSH
- Proteomics MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Basic Helix-Loop-Helix Transcription Factors genetics metabolism MeSH
- Transcription Factors genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
