HIV-1 accessory protein Vpr inhibits the effect of insulin on the Foxo subfamily of forkhead transcription factors by interfering with their binding to 14-3-3 proteins: potential clinical implications regarding the insulin resistance of HIV-1-infected patients.

Abstract	HIV-1 accessory protein Vpr arrests host cells at the G2/M phase of the cell cycle by interacting with members of the protein family 14-3-3, which regulate the activities of "partner" molecules by binding to their phosphorylated serine or threonine residues and changing their intracellular localization and/or stability. Vpr does this by facilitating the association of 14-3-3 to its partner protein Cdc25C, independent of the latter's phosphorylation status. Here we report that the same viral protein interfered with and altered the activity of another 14-3-3 partner molecule, Foxo3a, a subtype of the forkhead transcription factors, by inhibiting its association with 14-3-3. Foxo3a's transcriptional activity is normally suppressed by insulin-induced translocation of this protein from the nucleus into the cytoplasm. Vpr inhibited the ability of insulin or its downstream protein kinase Akt to change the intracellular localization of Foxo3a preferentially to the cytoplasm. This HIV-1 protein also interfered with insulin-induced coprecipitation of 14-3-3 and Foxo3a in vivo and antagonized the negative effect of insulin on Foxo3a-induced transactivation of a FOXO-responsive promoter. Moreover, Vpr antagonized insulin-induced suppression of the mRNA expression of the glucose 6-phosphatase, manganese superoxide dismutase, and sterol carrier protein 2 genes, which are known targets of insulin and FOXO, in HepG2 cells. These findings indicate that Vpr interferes with the suppressive effects of insulin on FOXO-mediated transcription of target genes via 14-3-3. Vpr thus may contribute to the tissue-selective insulin resistance often observed in HIV-1-infected individuals.
Authors	Tomoshige Kino, Massimo U De Martino, Evangelia Charmandari, Takamasa Ichijo, Taoufik Outas, George P Chrousos
Journal	Diabetes (Diabetes) Vol. 54 Issue 1 Pg. 23-31 (Jan 2005) ISSN: 0012-1797 [Print] United States
PMID	15616007 (Publication Type: Journal Article)
Chemical References	14-3-3 Proteins DNA-Binding Proteins FOXO1 protein, human Forkhead Box Protein O1 Forkhead Transcription Factors Fungal Proteins Gene Products, vpr Insulin Insulin Antagonists Proto-Oncogene Proteins Recombinant Fusion Proteins Transcription Factors Viral Proteins vpr Gene Products, Human Immunodeficiency Virus Cytochrome P-450 Enzyme System Mixed Function Oxygenases AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Topics	14-3-3 Proteins (metabolism) Acquired Immunodeficiency Syndrome (physiopathology) Cloning, Molecular Cytochrome P-450 Enzyme System DNA-Binding Proteins (antagonists & inhibitors) Forkhead Box Protein O1 Forkhead Transcription Factors Fungal Proteins Gene Products, vpr (pharmacology) HIV Infections (physiopathology) HIV-1 HeLa Cells Humans Insulin (pharmacology) Insulin Antagonists (pharmacology) Insulin Resistance (physiology) Mixed Function Oxygenases Protein Binding Protein Serine-Threonine Kinases (metabolism) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt Recombinant Fusion Proteins (metabolism) Transcription Factors (antagonists & inhibitors) Transfection Viral Proteins (pharmacology) vpr Gene Products, Human Immunodeficiency Virus

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!