Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

@article{Taipale2000EffectsOO,
  title={Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine},
  author={Jussi Taipale and James K. Chen and Michael K. Cooper and Baolin Wang and Randall K Mann and Ljiljana Milenkovic and Matthew P Scott and Philip A. Beachy},
  journal={Nature},
  year={2000},
  volume={406},
  pages={1005-1009}
}
Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tumours are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the Hh response pathway. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh… Expand
Patched acts catalytically to suppress the activity of Smoothened
TLDR
It is reported that Ptc and Smo are not significantly associated within Hh-responsive cells and it is suggested that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule. Expand
Cyclopamine as a potential therapeutic agent for treatment of tumors related to hedgehog pathway mutations.
  • Stanley J. Miller, Thomas C Yu
  • Biology, Medicine
  • Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]
  • 2002
TLDR
This work has identified the PTCH gene, a Drosophila segment polarity gene that encodes protein that is produced in a precise spatial pattern in developing flies and is thought to activate SMO by abolishing an otherwise repressive influence of PTCH. Expand
A synthetic combinatorial approach to disabling deviant Hedgehog signaling
TLDR
A small molecule SMO-HDAC antagonist (IHR-SAHA) retains inhibitory activity for GLI transcription induced bySMO-dependent and -independent mechanisms frequently associated with cancer biogenesis. Expand
Sonic hedgehog signaling in basal cell carcinomas.
TLDR
The molecular mechanisms involved in alterations of the hedgehog signaling pathway that lead to the formation of basal cell carcinomas are being unraveled and has already allowed the investigation of future therapeutic strategies for treating these skin cancers. Expand
Identification of a small molecule inhibitor of the hedgehog signaling pathway: Effects on basal cell carcinoma-like lesions
TLDR
A novel small molecule Hh inhibitor is identified that can block elevated Hh signaling activity resulting from oncogenic mutations in Patched-1 and can suppress proliferation and induce apoptosis of basaloid nests in the BCC model systems, whereas having no effect on normal skin cells. Expand
Calcitriol Inhibits Hedgehog Signaling and Induces Vitamin D Receptor Signaling and Differentiation in the Patched Mouse Model of Embryonal Rhabdomyosarcoma
TLDR
It is demonstrated that the treatment with the active form of vitamin D3, calcitriol, inhibits Hh signaling and proliferation of murine ERMS in vivo and in vitro and suggests that exogenous supply of calcitriols could be beneficial in the treatment of RMS, especially in those which are associated with Aberrant Hedgehog signaling activity. Expand
Inhibition of GLI1 gene activation by Patched1.
TLDR
It is shown that gene activation by GLI1, the transcriptional effector of the pathway, can be down-regulated by PTCH1 without involvement of the canonical cascade of HH signalling events. Expand
Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors
TLDR
The current and rapidly expanding field of SMO small-molecule inhibitors in experimental and clinical settings is reviewed, focusing on a class of acylguanidine derivatives, including mechanisms of resistance to SMO antagonists. Expand
Cyclopamine treatment of full‐blown Hh/Ptch‐associated RMS partially inhibits Hh/Ptch signaling, but not tumor growth
TLDR
The data indicate that there must be additional factors that render full‐blown Hh/Ptch‐associated RMS insensitive against anti‐proliferative effects of cyclopamine in vivo, and that this drug should not be routinely used in therapy of human RMS. Expand
Activation of Liver X Receptors Inhibits Hedgehog Signaling, Clonogenic Growth, and Self-Renewal in Multiple Myeloma
TLDR
The effects of LXR activation on Hh signaling in human multiple myeloma cells were examined and it was found that LXR agonists inhibited Hh pathway activity and clonogenic tumor growth in vitro. Expand
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  • Ronald L. Johnson, Alana L. Rothman, +8 authors Matthew P. Scott
  • Biology, Medicine
  • Science
  • 1996
TLDR
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TLDR
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TLDR
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