2015
DOI: 10.1074/jbc.m114.623264
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Zinc Inhibits Hedgehog Autoprocessing

Abstract: Background: In many types of cancers zinc deficiency and overproduction of Hedgehog (Hh) ligand co-exist. Results: Zinc binds to the active site of the Hedgehog-intein (Hint) domain and inhibits Hh ligand production both in vitro and in cell culture. Conclusion: Zinc influences the Hh autoprocessing.Significance: This study uncovers a novel mechanistic link between zinc and the Hh signaling pathway.

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Cited by 17 publications
(24 citation statements)
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“…[3b] Activity of SHhN–DHhC toward cholesterol has been established by SDS-PAGE analysis and mass spectrometry. [3b,14] Reactions of SHhN–DHhC in solutions containing A , G , or cholesterol monitored by SDS-PAGE are shown in Figure 2D. Consistent with the kinetic studies above, results indicate that both synthetic sterols stimulate processing of the precursor into SHhN–sterol and DHhC.…”
supporting
confidence: 81%
“…[3b] Activity of SHhN–DHhC toward cholesterol has been established by SDS-PAGE analysis and mass spectrometry. [3b,14] Reactions of SHhN–DHhC in solutions containing A , G , or cholesterol monitored by SDS-PAGE are shown in Figure 2D. Consistent with the kinetic studies above, results indicate that both synthetic sterols stimulate processing of the precursor into SHhN–sterol and DHhC.…”
supporting
confidence: 81%
“…Abnormal Hh autoprocessing in development leads to congenital diseases. Recently, we provided evidence that abnormal Hh autoprocessing may be linked to zinc deficiency 22 and metabolism of antiprostate cancer drugs. 23 Our results in this paper improve our understanding of Hh’s unique autoprocessing mechanism while providing a foothold 18 to correct aberrant Hh levels in developmental disorders and cancer.…”
Section: D46 Coordinates the Two Steps Through Side-chain Proton Shutmentioning
confidence: 99%
“…2,3 Cholesteroylation of Hh slows the rate of extracellular diffusion, giving rise to finely regulated signaling gradients during embryogenesis. 4 Mutagenesis studies show that abolishing cholesteroylation prevents Hh ligand secretion, resulting in the degradation of premature Hh ligand, and blockade of downstream signaling events.…”
mentioning
confidence: 99%
“…Conversely, ZNT transporters decrease cytosolic zinc. Altered zinc homeostasis may be permissive for PCa development, as zinc regulates crucial pathways involved in carcinogenesis including proliferation, apoptosis, and cellular metabolism 3 , 10 , 11 . In PCa cells, zinc inhibits proliferation by blocking the G2/M cell cycle check point 12 , and is pro-apoptotic by several mechanisms including increased Bax/BCL-2 ratio 13 and decreased NF-κB leading to caspase 3/7 activation 14 .…”
Section: Introductionmentioning
confidence: 99%