Regulation of the ferredoxin component of renal hydroxylases at transcriptional and postranslational levels and of the protein inhibitor of cyclic AMP-dependent kinase.
We have studied two proteins potentially involved in the regulation of the 25-OH-D-1-hydroxylase, which is located in the renal mitochondria and which is responsible for the production of the steroid hormone 1,25(OH)2D3. The endogenous inhibitor of cyclic AMP-dependent protein kinase, PKI, is down regulated by 1,25(OH)2D3. Having cloned and sequenced PKI cDNA, we studied its message levels and found them to be regulated by 1,25(OH)2D3 tissue specifically in the kidney and in kidney cell culture. In other experiments we over expressed the ferredoxin component of the 1-hydroxylase and found it to be physically and chemically indistinguishable from those of classic steroidogenic tissues. The mRNA encoding the ferredoxin component is up-regulated by chronic vitamin D deficiency, which at the same time leads to sustained elevation in 1-hydroxylase activity; no short term effect of 1,25(OH)2D3 on ferredoxin mRNA in kidney cell culture could be demonstrated. Finally, there was an association between decreased phosphorylation of ferredoxin and decreased 1-hydroxylase activity brought about by treatment of cultured kidney cells with TPA. Control of the renal signaling events involved in the production of 1,25(OH)2D3 remains a fruitful area of investigation in the field of the metabolism and actions of vitamin D and its metabolites.
Henry
H L
HL
Department of Biochemistry, University of California, Riverside 92521, USA.
Tang
C
C
Blanchard
R
R
Marchetto
G S
GS
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002645:Chickens; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D005288:Ferredoxins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000201:enzymology*; D008928:Mitochondria / Q000201:enzymology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D002352:Carrier Proteins; D005288:Ferredoxins; D047908:Intracellular Signaling Peptides and Proteins; C015482:protein kinase modulator; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate