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Hedgehog Signaling Pathway (hedgehog + signaling_pathway)
Selected AbstractsA Small-Molecule Antagonist of the Hedgehog Signaling PathwayCHEMBIOCHEM, Issue 16 2007Jongkook Lee Dr. Shadow the Hedgehog. JK184 (illustrated in the scheme) was identified as an antagonist of Hedgehog signaling through a cell-based screen of chemical libraries. Results from biochemical and cellular experiments suggest that JK184 functions by inhibiting class IV alcohol dehydrogenase. This molecule should serve as a useful tool for studying Hedgehog signaling. [source] Small-Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer TherapeuticsCHEMMEDCHEM, Issue 4 2010Stefan Peukert Dr. Abstract Inhibitors of the Hedgehog (Hh) molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof-of-concept studies have been carried out in patients with defined genetic mutations in the Hh pathway. This review provides a general overview of three main topics in this rapidly expanding area: 1),the various types of biological assays and in,vivo models that have been employed for the identification and optimization of Hh pathway inhibitors; 2),Smo inhibitors reported to date, including recent clinical results where available; and 3),efforts toward the identification and characterization of inhibitors of other members of the Hh pathway. [source] Gli3 null mice display glandular overgrowth of the developing stomachDEVELOPMENTAL DYNAMICS, Issue 4 2005Jae H. Kim Abstract The role of the Hedgehog signaling pathway in various aspects of gut development is still poorly understood. In the developing stomach, Sonic (Shh) and Indian (Ihh) hedgehog are expressed in both distinct and overlapping regions. Loss of Sonic hedgehog function in the stomach results in a glandular phenotype of intestinal transformation and overgrowth. These changes are reminiscent of the pre-malignant lesion, intestinal metaplasia. To determine the role of Hedgehog-related transcription factors, Gli2 and Gli3, in Shh signaling during stomach development, we conducted a mutant analysis of glandular stomach from Shh, Gli2, and Gli3 mutant mice. Although Gli2 principally mediates the activator function of Shh, surprisingly we observed minimal changes in glandular development in the Gli2 mutant stomach. Furthermore, Gli3, which typically functions as a repressor of Hedgehog signal, showed a striking phenocopy of the glandular expansion and intestinal transformation found in Shh mutant stomach. A reduction in apoptotic events was seen in all mutant stomachs with no appreciable changes in proliferation. Both Shh and Gli3 mutant stomachs displayed early changes of intestinal transformation but these did not impact on the overall differentiation of the gastric epithelium. Interestingly, the observation that Gli3 shares a similar glandular phenotype to Shh mutant stomach reveals a possible novel role of Gli3 activator in the developing stomach. The embryonic stomach is a unique model of the Hedgehog pathway function and one that may help to uncover some of the mechanisms underlying the development of intestinal metaplasia. Developmental Dynamics 234:984,991, 2005. © 2005 Wiley-Liss, Inc. [source] Ptc, Smo, Sufu, and the Hedgehog signaling pathway in amphioxusEVOLUTION AND DEVELOPMENT, Issue 6 2009Yushuang Lin SUMMARY The Hedgehog (Hh) signaling pathway regulates many developmental processes both in vertebrates and in invertebrates. However, little is known about this pathway in the cephalochordate amphioxus. In this paper, we focus on the Ptc, Smo, and Sufu homologs in amphioxus, which are the key members of the Hh signaling pathway. Their genomic structures show their comparability with homologs in vertebrates. In situ hybridization reveals that amphioxus Ptc, Smo, and Sufu have similar expression patterns in embryogenesis. They are expressed in the neural plate at early neurula stage, and then down-regulated in dorsal neural ectoderm. During development, their transcripts appear and persist in the notochord, the wall of the head cavity, the epithelium of the pharynx, and the gut. The data show that the expression patterns of these three genes are overlapping with Hh and Gli during the embryonic development in amphioxus. Moreover, injection of amphioxus Hh RNA into zebrafish-fertilized eggs can expand the expression domains of Ptc1 and Nk2.2a, the target genes of the Hh signaling pathway, which is similar to the injection of zebrafish Sonic hh a (zShha) and Sonic hh b (zShhb). Our results suggest that amphioxus may possess a conserved and functional Hh signaling pathway similar to that of vertebrates. [source] Tumor suppressor gene Co-operativity in compound Patched1 and suppressor of fused heterozygous mutant miceMOLECULAR CARCINOGENESIS, Issue 5 2009Jessica Svärd Abstract Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1+/, mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu+/, mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu+/,Ptch1+/, mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu+/,Ptch1+/, compared to Sufu+/, female, but not male, mice. For medulloblastoma, the cumulative 1-yr incidence was 1.5-fold higher in Sufu+/,Ptch1+/, compared to Ptch1+/, female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu+/,Ptch1+/, mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in ,20% of the Ptch1+/, and Sufu+/,Ptch1+/, but not in Sufu+/, mice. Interestingly, most of the medulloblastomas from the Sufu+/,Ptch1+/, mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1+/, and Sufu+/,Ptch1+/, mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway. © 2008 Wiley-Liss, Inc. [source] Oxysterol-induced osteogenic differentiation of marrow stromal cells is regulated by Dkk-1 inhibitable and PI3-kinase mediated signalingJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2008Christopher M. Amantea Abstract Osteoporosis and its complications cause morbidity and mortality in the aging population, and result from increased bone resorption by osteoclasts in parallel with decreased bone formation by osteoblasts. A widely accepted strategy for improving bone health is targeting osteoprogenitor cells in order to stimulate their osteogenic differentiation and bone forming properties through the use of osteoinductive/anabolic factors. We previously reported that specific naturally occurring oxysterols have potent osteoinductive properties, mediated in part through activation of hedgehog signaling in osteoprogenitor cells. In the present report, we further demonstrate the molecular mechanism(s) by which oxysterols induce osteogenesis. In addition to activating the hedgehog signaling pathway, oxysterol-induced osteogenic differentiation is mediated through a Wnt signaling-related, Dkk-1-inhibitable mechanism. Bone marrow stromal cells (MSC) treated with oxysterols demonstrated increased expression of osteogenic differentiation markers, along with selective induced expression of Wnt target genes. These oxysterol effects, which occurred in the absence of ,-catenin accumulation or TCF/Lef activation, were inhibited by the hedgehog pathway inhibitor, cyclopamine, and/or by the Wnt pathway inhibitor, Dkk-1. Furthermore, the inhibitors of PI3-Kinase signaling, LY 294002 and wortmanin, inhibited oxysterol-induced osteogenic differentiation and induction of Wnt signaling target genes. Finally, activators of canonical Wnt signaling, Wnt3a and Wnt1, inhibited spontaneous, oxysterol-, and Shh-induced osteogenic differentiation of bone marrow stromal cells, suggesting the involvement of a non-canonical Wnt pathway in pro-osteogenic differentiation events. Osteogenic oxysterols are, therefore, important small molecule modulators of critical signaling pathways in pluripotent mesenchymal cells that regulate numerous developmental and post-developmental processes. J. Cell. Biochem. 105: 424,436, 2008. © 2008 Wiley-Liss, Inc. [source] Gene expression profiles of lens regeneration and development in Xenopus laevisDEVELOPMENTAL DYNAMICS, Issue 9 2009Erica L. Malloch Abstract Seven hundred and thirty-four unique genes were recovered from a cDNA library enriched for genes up-regulated during the process of lens regeneration in the frog Xenopus laevis. The sequences represent transcription factors, proteins involved in RNA synthesis/processing, components of prominent cell signaling pathways, genes involved in protein processing, transport, and degradation (e.g., the ubiquitin/proteasome pathway), matrix metalloproteases (MMPs), as well as many other proteins. The findings implicate specific signal transduction pathways in the process of lens regeneration, including the FGF, TGF-beta, MAPK, Retinoic acid, Wnt, and hedgehog signaling pathways, which are known to play important roles in eye/lens development and regeneration in various systems. In situ hybridization revealed that the majority of genes recovered are expressed during embryogenesis, including in eye tissues. Several novel genes specifically expressed in lenses were identified. The suite of genes was compared to those up-regulated in other regenerating tissues/organisms, and a small degree of overlap was detected. Developmental Dynamics 238:2340,2356, 2009. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||