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J. Biol. Chem., Vol. 278, Issue 8, 5646-5651, February 21, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/8/5646    most recent M211750200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singh, D. K. Articles by Porter, T. D. Search for Related Content PubMed PubMed Citation Articles by Singh, D. K. Articles by Porter, T. D. Social Bookmarking                      What's this?

Phosphorylation of Supernatant Protein Factor Enhances Its Ability to Stimulate Microsomal Squalene Monooxygenase^*

Dev K. Singh, Vishwesh Mokashi^§, C. Lee Elmore^§¶, and Todd D. Porter^§

From the  Division of Pharmaceutical Sciences, College of Pharmacy and ^§ The Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536-0082

Supernatant protein factor is a 46-kDa cytosolic protein that stimulates squalene monooxygenase, a downstream enzyme in the cholesterol biosynthetic pathway. The mechanism of stimulation is poorly understood, although supernatant protein factor belongs to a family of lipid-binding proteins that includes Sec14p and -tocopherol transfer protein. Because recombinant human supernatant protein factor purified from Escherichia coli exhibited a relatively weak ability to activate microsomal squalene monooxygenase, we investigated the possibility that cofactors or post-translational modifications were necessary for full activity. Addition of ATP to rat liver cytosol increased supernatant protein factor activity by more than 2-fold and could be prevented by the addition of inhibitors of protein kinases A and C. Incubation of purified recombinant supernatant protein factor with ATP and protein kinases A or C similarly increased activity by more than 2-fold. Addition of protein phosphatase 1, a serine/threonine phosphatase, to rat liver cytosol reduced activity by 50%, suggesting that supernatant protein factor is partially phosphorylated in vivo. To determine whether dietary cholesterol influenced the phosphorylation state, cytosols were prepared from livers of rats fed a high fat diet. Although supernatant protein factor activity was reduced by more than one-half, it could not be restored by the addition of ATP or protein kinase C with ATP, suggesting that dietary cholesterol reduced the expression of this protein. Supernatant protein factor thus appears to be regulated both post-translationally through phosphorylation and at the level of expression. Phosphorylation may provide a means for the rapid short term modulation of cholesterol synthesis.

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