Teratogenic compounds of Veratrum californicum (Durand). X. Cyclopia in rabbits produced by cyclopamine
TL;DR: Both in vitro and in vivo experiments suggested the conversion of nonbuffered cyclopamine to veratramine under stomach-acid conditions.
Abstract: Cyclopamine, the compound responsible for cyclopia in sheep upon maternal ingestion of Veratrum californicum, produced cyclopia and related cephalic malformations in rabbits when orally administered with CaCO3 as a stomach-acid buffer to prevent acid-induced conversion to veratramine, a compound devoid of similar teratogenic activity. The insult period was between days 6 and 9 of gestation. Both in vitro and in vivo experiments suggested the conversion of nonbuffered cyclopamine to veratramine under stomach-acid conditions.
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TL;DR: It is demonstrated that small molecules capable of conditional gene product modulation can be identified through developmental screens in zebrafish, and several of the small molecules identified allowed us to dissect the logic of melanocyte and otolith development and to identify critical periods for these events.
Abstract: Much has been learned about vertebrate development by random mutagenesis followed by phenotypic screening and by targeted gene disruption followed by phenotypic analysis in model organisms. Because the timing of many developmental events is critical, it would be useful to have temporal control over modulation of gene function, a luxury frequently not possible with genetic mutants. Here, we demonstrate that small molecules capable of conditional gene product modulation can be identified through developmental screens in zebrafish. We have identified several small molecules that specifically modulate various aspects of vertebrate ontogeny, including development of the central nervous system, the cardiovascular system, the neural crest, and the ear. Several of the small molecules identified allowed us to dissect the logic of melanocyte and otolith development and to identify critical periods for these events. Small molecules identified in this way offer potential to dissect further these and other developmental processes and to identify novel genes involved in vertebrate development.
501 citations
TL;DR: A key and essential role is indicated in promoting CC growth, stem cell self‐renewal and metastatic behavior in advanced cancers and Targeting HH‐GLI1, directly or indirectly, is predicted to decrease tumour bulk and eradicate CC stem cells and metastases.
Abstract: Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced beta CATENIN (beta CAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of CC stem cells in vivo relies on HH-GLI activity. Our results indicate a key and essential role of the HH-GLI1 pathway in promoting CC growth, stem cell self-renewal and metastatic behavior in advanced cancers. Targeting HH-GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases.
446 citations
Cites methods from "Teratogenic compounds of Veratrum c..."
...…an additional test for the requirement of HH-GLI function, we also inhibited SMOH pharmacologically by treatment with cyclopamine, a plant alkaloid (Keeler, 1970, 1978) that inhibits SMOH (Cooper et al, 1998; Incardona et al, 1998) and that we found to be a specific inhibitor of HH-GLI at…...
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TL;DR: A balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other, and 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.
Abstract: 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.
437 citations
TL;DR: The Gli code hypothesis postulates that the three vertebrate Gli transcription factors act together in responding cells to integrate intercellular Hedgehog and other signaling inputs, resulting in the regulation of tissue pattern, size and shape.
379 citations
TL;DR: A brief overview of HH signaling and the key molecular players involved is provided and an up-to-date summary of the current knowledge of endogenous and exogenous small molecules that modulate HH signaling is offered.
231 citations
References
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Journal Article•
192 citations
TL;DR: Cyclopamine, and its glycoside alkaloid X, along with jervine and veratrosine, induced cyclopian malformations in offspring born to ewes ingesting these compounds on the fourteenth day of gestation.
Abstract: Cyclopamine, and its glycoside alkaloid X, along with jervine and veratrosine, induced cyclopian malformations in offspring born to ewes ingesting these compounds on the fourteenth day of gestation. Other steroidal alkaloids with somewhat similar structures and various other steroidal compounds including certain hormones and steroidal sapogenins did not induce the malformation.
151 citations
59 citations
TL;DR: The isolation and identification of four known alkaloids (jervine, veratrosine, pseudojervin, and isorubijervine) was achieved from teratogenic fractions of Veratrum californicum.
Abstract: The isolation and identification of four known alkaloids (jervine, veratrosine, pseudojervine, and isorubijervine) was achieved from teratogenic fractions of Veratrum californicum. Two additional alkaloids, not previously reported and herein designated alkaloids X and V, were also isolated from these fractions and partially characterized.
56 citations
TL;DR: The structures and configurations of three naturally occurring steroidal alkaloid teratogens from Veratrum californicum that induce cyclopia in sheep have been elucidated and methods are proposed to enable elucidation of the precise structural requirements for this teratogenic effect.
Abstract: The structures and configurations of three naturally occurring steroidal alkaloid teratogens from Veratrum californicum that induce cyclopia in sheep have been elucidated. The probable teratogenic structural requirements were examined in light of known structural and configurational information on active and nonactive compounds. Methods are proposed that will enable elucidation of the precise structural requirements for this teratogenic effect.
46 citations