Cyclopamine inhibition of sonic hedgehog signal transduction is not mediated through effects on cholesterol transport

被引:97
作者
Incardona, JP
Gaffield, W
Lange, Y
Cooney, A
Pentchev, PG
Liu, S
Watson, JA
Kapur, RP
Roelink, H
机构
[1] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA
[2] Univ Washington, Ctr Dev Biol, Seattle, WA 98195 USA
[3] Univ Washington, Dept Pathol, Seattle, WA 98195 USA
[4] ARS, Western Reg Res Ctr, USDA, Albany, CA 94710 USA
[5] Rush Presbyterian St Lukes Med Ctr, Dept Pathol, Chicago, IL 60612 USA
[6] NINDS, Dev & Metab Neurobiol Branch, NIH, Bethesda, MD 20892 USA
[7] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA
关键词
neural development; holoprosencephaly; teratogen; U18666A; progesterone; membrane trafficking;
D O I
10.1006/dbio.2000.9775
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cyclopamine is a teratogenic steroidal alkaloid that causes cyclopia by blocking Sonic hedgehog (Shh) signal transduction. We have tested whether this activity of cyclopamine is related to disruption of cellular cholesterol transport and putative secondary effects on the Shh receptor, Patched (Ptc). First, we report that the potent antagonism of Shh signaling by cyclopamine is not a general property of steroidal alkaloids with similar structure. The structural features of steroidal alkaloids previously associated with the induction of holoprosencephaly in whole animals are also associated with inhibition of Shh signaling in vitro. Second, by comparing the effects of cyclopamine on Shh signaling with those of compounds known to block cholesterol transport, we show that the action of cyclopamine cannot be explained by inhibition of intracellular cholesterol transport. However, compounds that block cholesterol transport by affecting the vesicular trafficking of the Niemann-Pick C1 protein (NPC1), which is structurally similar to Ptc, are weak Shh antagonists. Rather than supporting a direct link between cholesterol homeostasis and Shh signaling, our findings suggest that the functions of both NPC1 and Ptc involve a common vesicular transport pathway. Consistent with this model, we find that Ptc and NPC1 colocalize extensively in a vesicular compartment in cotransfected cells. (C) 2000 Academic Press.
引用
收藏
页码:440 / 452
页数:13
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