Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cement gland is a mucus-secreting organ found at the extreme anterior of frog embryos. It attaches the embryo to a solid support before swimming and feeding begin, and also serves a related sensory function that stops the embryo from moving once it is attached. Cement gland is an extremely useful anterior marker, whose study continues to yield fundamental information concerning vertebrate axial patterning. Cement gland arises from the outer layer of the embryonic ectoderm and, in Xenopus, forms a cone of columnar epithelium. It is the first ectodermal organ to differentiate, beginning to do so by late gastrula. A battery of genes expressed in the developing and mature cement gland serve as useful markers. Cement gland development can be influenced by both stimulatory and inhibitory cell interactions. Stimulatory signals arise from the anterior neural plate, head endoderm, and the dorsal mesoderm. Inhibitory signals are present in the posterior dorsal mesoderm and in ventral ectoderm and mesoderm. Further, signalling between the ectodermal layers may restrict cement gland differentiation to the outer ectodermal cells. Several secreted molecules are able to induce or repress cement gland formation: these include noggin, follistatin, hedgehog, chordin, retinoic acid, embryonic fibroblast growth factor (eFGF), Bone Morphogenetic Protein-4 (BMP-4), and Xwnt-8. Several of these factors alter expression of the homeodomain gene Xotx2, which may be a transcriptional activator of cement gland differentiation genes. The significance of the cell interactions and factors described in positioning cement gland at the front of the embryo is explored.
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PMID:A sticky problem: the Xenopus cement gland as a paradigm for anteroposterior patterning. 885 May 63

Truncation mutations of the GLI3 zinc finger transcription factor can cause Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS), and postaxial polydactyly type A (PAP-A). GLI3 is homologous to Drosophila Cubitus interruptus (Ci), which regulates the patched (ptc), gooseberry (gsb), and decapentaplegic (dpp) genes. Ci is sequestered in the cytoplasm and is subject to posttranslational processing whereby the full-length transcriptional activator form (Ci155) can be cleaved to a repressor form (Ci75). Under hedgehog signaling, the Ci155 form translocates to the nucleus whereas in the absence of hedgehog, the Ci75 form translocates to the nucleus. Based on the correlation of GLI3 truncation mutations and the human phenotypes, we hypothesized that GLI3 shows transcriptional activation or repression activity and subcellular localization similar to Ci. Here we show that full-length GLI3 localizes to the cytoplasm and activates PTCH1 expression, which is similar to full-length Ci155. PHS mutant protein (GLI3-PHS) localizes to the nucleus and represses GLI3-activated PTCH1 expression, which is similar to Ci75. The GCPS mutant protein has no effect on GLI3-activated PTCH1 transcription, consistent with the role of haploinsufficiency in this disorder. The PAP-A mutant protein (GLI3-PAP-A) showed less specific subcellular localization but still inhibited GLI3-activated PTCH1 transcription, suggesting it may be a weaker allele than the GLI3-PHS mutation. These data show that GLI3 mutations in humans mimic functional effects of the Drosophila ci gene and correlate with the distinct effects of these mutations on human development.
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PMID:GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. 1007 5

Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling in vertebrates. The question remains unanswered, however, as to how these Gli proteins participate in the Shh signaling pathway. In this study, regulatory activities associated with the Gli2 protein were investigated in relation to the Shh signaling. Although Gli2 acts as a weak transcriptional activator, it is in fact a composite of positive and negative regulatory domains. In cultured cells, truncation of the activation domain in the C-terminal half results in a protein with repressor activity, while removal of the repression domain at the N terminus converts Gli2 into a strong activator. In transgenic mouse embryos, N-terminally truncated Gli2, unlike the full length protein, activates a Shh target gene, HNF3beta, in the dorsal neural tube, thus mimicking the effect of Shh signal. This suggests that unmasking of the strong activation potential of Gli2 through modulation of the N-terminal repression domain is one of the key mechanisms of the Shh signaling. A similar regulatory mechanism involving the N-terminal region was also found for Gli3, but not for Gli1. When the Shh signal derived from the notochord is received by the neural plate, the widely expressed Gli2 and Gli3 proteins are presumably converted to their active forms in the ventral cells, leading to activation of transcription of their target genes, including Gli1.
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PMID:Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. 1043 19

Most current models propose Sonic hedgehog (Shh) as the primary determinant of anteroposterior development of amniote limbs. Shh protein is said to be required to direct the formation of skeletal elements and to specify digit identity through dose-dependent activation of target gene expression. However, the identity of genes targeted by Shh, and the regulatory mechanisms controlling their expression, remain poorly understood. Gli3 (the gene implicated in human Greig cephalopolysyndactyly syndrome) is proposed to negatively regulate Shh by restricting its expression and influence to the posterior mesoderm. Here we report genetic analyses in mice showing that Shh and Gli3 are dispensable for formation of limb skeletal elements: Shh(-/-) Gli3(-/-) limbs are distally complete and polydactylous, but completely lack wild-type digit identities. We show that the effects of Shh signalling on skeletal patterning and ridge maintenance are necessarily mediated through Gli3. We propose that the function of Shh and Gli3 in limb skeletal patterning is limited to refining autopodial morphology, imposing pentadactyl constraint on the limb's polydactyl potential, and organizing digit identity specification, by regulating the relative balance of Gli3 transcriptional activator and repressor activities.
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PMID:Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. 1219 47

Although much has been learned about growth plate development and chondrocyte gene expression during cellular maturation and matrix remodeling in the mouse, there has been a limited study of the interrelationships of gene expression between proteinases, growth factors, and other regulatory molecules in the mouse and in other species. Here we use RT-PCR of sequential transverse sections to examine the expression profiles of genes involved in chondrocyte growth, differentiation, matrix assembly, remodeling, and mineralization in the bovine proximal tibial growth plate. Specifically, we studied the expression of genes encoding COL2A1 and COL10A1, the latter a marker of cellular hypertrophy, the matrix metalloproteinases (MMP), MMP-13 and MMP-9, as well as the transcriptional factors, Sox9 and Cbfa1, the growth factors basic fibroblast growth factor (bFGF), parathyroid hormone-related peptide (PTHrP), transforming growth factor (TGF)beta1, and beta2, Indian hedgehog (Ihh), and the matrix protein osteocalcin. These were analyzed in relationship to cell division defined by cyclin B2 expression. Two peaks of gene expression activity were observed. One was transient, limited, and located immediately before and at the onset of cyclin B2 expression in the early proliferative zone. The other was generally much more pronounced and was located in the early hypertrophic zone. The upregulation of expression of COL2A1, its transcriptional activator Sox9, osteocalcin, MMP-13, and TGFbeta2 was observed immediately before and at the onset of cyclin B2 expression and also in the hypertrophic zones. The upregulation of COL10A1, Cbfa1, MMP-9, TGFbeta-1, and Ihh gene expression was associated exclusively with the terminal differentiation of chondrocytes at the time of mineral formation in the extracellular matrix. In contrast, bFGF and PTHrP expression was observed in association with the onset of cyclin B2 expression and hypertrophy. This initial cluster of gene expression associated predominantly with matrix assembly and onset of cell proliferation is therefore characterized by expression of regulatory molecules distinct from those involved at hypertrophy. Together these results identify separate phases of coordinated gene expression associated with the development of the physis in endochondral bone formation.
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PMID:Distinct phases of coordinated early and late gene expression in growth plate chondrocytes in relationship to cell proliferation, matrix assembly, remodeling, and cell differentiation. 1273 23

In the hedgehog signaling network, mutations result in various phenotypes, including, among others, holoprosencephaly, nevoid basal cell carcinoma syndrome, Pallister-Hall syndrome, Greig cephalopolysyndactyly, Rubinstein-Taybi syndrome, isolated basal cell carcinoma, and medulloblastoma. Active Hedgehog ligand is double lipid modified with a C-terminal cholesterol moiety and an N-terminal palmitate. Transport active Hedgehog from the signaling cell to the responding cell occurs through three mechanisms: 1). formation of multimeric Hedgehog which makes it soluble; 2). function of Dispatched in releasing the lipid-anchored protein from the signaling cell; and 3). movement across the plasma membrane of the responding cell by Tout-velu-dependent synthesis of heparan sulfate proteoglycan. In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling. Patched and Smoothened may shuttle oppositely between the plasma membrane and endocytic vesicles in response to active Hedgehog ligand. In downstream signaling, Cubitus interruptus (Gli proteins in vertebrates), Costal 2, Fused, and Suppressor of Fused form a tetrameric complex. Cubitus interruptus is a bifunctional transcription regulator. In the absence of active Hedgehog ligand, a truncated transcriptional repressor is generated that binds target genes and blocks their transcription. In the presence of active Hedgehog ligand, a full length transcriptional activator binds target genes and upregulates their transcription. Target genes include Wingless (Wnt gene family in vertebrates), Decapentaplegic (Bone Morphogenetic Proteins in vertebrates), and Patched. The upregulation of Patched expression, resulting in Patched protein at the cell membrane, sequesters Hedgehog and limits its spread beyond the cells in which it is produced. Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. Many more factors that are essential for the hedgehog signaling network are also discussed: Megalin, Rab23, Hip, GAS1, PKA, GSK3, CK1, Slimb, SAP18, and CBP.
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PMID:The hedgehog signaling network. 1455 42

Gli2 and Gli3 are the primary transcription factors that mediate Sonic hedgehog (Shh) signals in the mouse. Gli3 mainly acts as a transcriptional repressor, because the majority of full-length Gli3 protein is proteolytically processed. Gli2 is mostly regarded as a transcriptional activator, even though it is also suggested to have a weak repressing activity. What the molecular basis for its possible dual function is and how its activity is regulated by Shh signaling are largely unknown. Here we demonstrate that unlike the results seen with Gli3 and Cubitus Interruptus, the fly homolog of Gli, only a minor fraction of Gli2 is proteolytically processed to form a transcriptional repressor in vivo and that in addition to being processed, Gli2 full-length protein is readily degraded. The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. The phosphorylated Gli2 interacts directly with betaTrCP in the SCF ubiquitin-ligase complex through two binding sites, which results in Gli2 ubiquitination and subsequent degradation by the proteasome. Both processing and degradation of Gli2 are suppressed by Shh signaling in vivo. Our findings provide the first demonstration of a molecular mechanism by which the Gli2 transcriptional activity is regulated by Shh signaling.
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PMID:Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. 1661 81

Telencephalic patterning centers, defined by the discrete expression domains of distinct morphogens, Fgfs in the commissural plate (CoP), Wnts and Bmps in the cortical hem, and a ventral domain of Sonic hedgehog (Shh), are postulated to establish during development the initial patterning of the telencepahlon, including the neocortex. We show that the expression patterns of Sp5, Sp8, and Sp9, members of the Sp8-like family that are homologues of Drosophila buttonhead, correlate during early embryonic development with these three telencephalic patterning centers. To study potential functional relationships, we focused on Sp8, because it is transiently expressed in the CoP coincident with the expression of Fgf8, a morphogen implicated in area patterning of the neocortex. We also show that Sp8 is expressed in cortical progenitors in a high to low anterior-medial to posterior-lateral gradient across the ventricular zone. We used in utero electroporation of full-length and chimeric expression constructs to perform gain-of-function and loss-of-function studies of interactions between Sp8 and Fgf8 and their roles in cortical area patterning. We show that Fgf8 and Sp8 exhibit reciprocal induction in vivo in the embryonic telencephalon. Sp8 also induces downstream targets of Fgf8, including ETS transcription factors. In vitro assays show that Sp8 binds Fgf8 regulatory elements and is a direct transcriptional activator of Fgf8. We also show that Sp8 induction of Fgf8 is repressed by Emx2 in vitro, suggesting a mechanism to limit Fgf8 expression to the CoP. In vivo expression of a dominant negative Sp8 in the CoP indicates that Sp8 maintains expression of Fgf8 and also its effect on area patterning. Ectopic expression of Sp8 in anterior or posterior cortical poles induces significant anterior or posterior shifts in area patterning, respectively, paralleled by changes in expression of gene markers of positional identity. These effects of Sp8 on area patterning oppose those induced by ectopic expression of Fgf8, suggesting that in parallel to regulating Fgf8 expression, Sp8 also activates a distinct signaling pathway for cortical area patterning. In summary, Sp8 and Fgf8 robustly induce one another, and may act to balance the anterior-posterior area patterning of the cortex.
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PMID:Sp8 exhibits reciprocal induction with Fgf8 but has an opposing effect on anterior-posterior cortical area patterning. 1750 51

The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay. We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystaurosporinone (10), arcyriaflavin C (11) and 5,6-dihydroxyarcyriaflavin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physalins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that 1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis Bcl2 expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.
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PMID:Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. 1835 92

Activating transcription factor 4 (Atf4) is a leucine-zipper-containing protein of the cAMP response element-binding protein (CREB) family. Ablation of Atf4 (Atf4(-/-)) in mice leads to severe skeletal defects, including delayed ossification and low bone mass, short stature and short limbs. Atf4 is expressed in proliferative and prehypertrophic growth plate chondrocytes, suggesting an autonomous function of Atf4 in chondrocytes during endochondral ossification. In Atf4(-/-) growth plate, the typical columnar structure of proliferative chondrocytes is disturbed. The proliferative zone is shortened, whereas the hypertrophic zone is transiently expanded. The expression of Indian hedgehog (Ihh) is markedly decreased, whereas the expression of other chondrocyte marker genes, such as type II collagen (Col2a1), PTH/PTHrP receptor (Pth1r) and type X collagen (Col10a1), is normal. Furthermore, forced expression of Atf4 in chondrocytes induces endogenous Ihh mRNA, and Atf4 directly binds to the Ihh promoter and activates its transcription. Supporting these findings, reactivation of Hh signaling pharmacologically in mouse limb explants corrects the Atf4(-/-) chondrocyte proliferation and short limb phenotypes. This study thus identifies Atf4 as a novel transcriptional activator of Ihh in chondrocytes that paces longitudinal bone growth by controlling growth plate chondrocyte proliferation and differentiation.
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PMID:Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription. 1990 42


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