Inhibition of aldosterone biosynthesis by staurosporine
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Matthias Bureik
Abstract
Staurosporine (STS) is a very potent broad-range kinase inhibitor, and its antiproliferative properties made it a lead compound for protein kinase C (PKC) inhibitors with therapeutic potential. Because STS also causes hypotension, we investigated in this study whether it directly interferes with the terminal steps of aldosterone biosynthesis; these are catalysed by a mitochondrial steroid hydroxylase system consisting of adrenodoxin reductase, adrenodoxin, and the cytochrome P450 enzyme hCYP11B2 (aldosterone synthase). Here we demonstrate that nanomolar concentrations of STS significantly reduced aldosterone synthase activity in transiently transfected COS-1 cells and in stably transfected V79MZh11B2 cells (IC50=11 nM). However, STS did not inhibit bovine aldosterone synthase in a reconstituted steroid hydroxylation assay. In transiently transfected COS-1 cells, the protein level of adrenodoxin (but not that of adrenodoxin reductase or of hCYP11B2) was significantly reduced after treatment with 2 nM STS. Finally, we show that STS treatment (1 μg/day) of mice reduced their aldosterone/renin ratio by almost 50% (p=0.015). To the best of our knowledge, this is the first report of a direct in vivo effect of STS on the renin-angiotensin-aldosterone system. We conclude (i) that the hypotensive effect of staurosporine is at least partly due to inhibition of aldosterone biosynthesis via adrenodoxin depletion, and (ii) that aldosterone biosynthesis can be regulated in vivo at the level of adrenodoxin availability.
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Artikel in diesem Heft
- Digestive versus regulatory proteases: on calpain action in vivo
- Psc3 cohesin of Schizosaccharomyces pombe: cell cycle analysis and identification of three distinct isoforms
- Rearrangements in a hydrophobic core region mediate cAMP action in the regulatory subunit of PKA
- Characterization of oligomeric species in the fibrillization pathway of the yeast prion Ure2p
- Nucleotide binding and filament assembly of recombinant yeast septin complexes
- Identification and partial characterization of two eukaryotic UDP-galactopyranose mutases
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- Rab6 interacts with the mint3 adaptor protein
- Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37)
- Kinetics of autocatalytic zymogen activation measured by a coupled reaction: pepsinogen autoactivation
- A possible alternative mechanism of kinin generation in vivo by cathepsin L
- hDLG/SAP97, a member of the MAGUK protein family, is a novel caspase target during cell-cell detachment in apoptosis