PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP.
Protein kinase B (PKB/Akt) has been shown to play a role in protection from apoptosis, cell proliferation and cell growth. It is also involved in mediating the effects of insulin, such as lipogenesis, glucose uptake and conversion of glucose into fatty acids and cholesterol. Sterol-regulatory element binding proteins (SREBPs) are the major transcription factors that regulate genes involved in fatty acid and cholesterol synthesis. It has been postulated that constitutive activation of the phosphatidylinositol 3 kinase/Akt pathway may be involved in fatty acid and cholesterol accumulation that has been described in several tumour types. In this study, we have analysed changes in gene expression in response to Akt activation using DNA microarrays. We identified several enzymes involved in fatty acid and cholesterol synthesis as targets for Akt-regulated transcription. Expression of these enzymes has previously been shown to be regulated by the SREBP family of transcription factors. Activation of Akt induces synthesis of full-length SREBP-1 and SREBP-2 proteins as well as expression of fatty acid synthase (FAS), the key regulatory enzyme in lipid biosynthesis. We also show that Akt leads to the accumulation of nuclear SREBP-1 but not SREBP-2, and that activation of SREBP is required for Akt-induced activation of the FAS promoter. Finally, activation of Akt induces an increase in the concentration of cellular fatty acids as well as phosphoglycerides, the components of cellular membranes. Our data indicate that activation of SREBP by Akt leads to the induction of key enzymes of the cholesterol and fatty acid biosynthesis pathways, and thus membrane lipid biosynthesis.
Porstmann
Thomas
T
Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Griffiths
Beatrice
B
Chung
Yuen-Li
YL
Delpuech
Oona
O
Griffiths
John R
JR
Downward
Julian
J
Schulze
Almut
A
D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D020869:Gene Expression Profiling; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004798:Enzymes; D005227:Fatty Acids; D007328:Insulin; D011518:Proto-Oncogene Proteins; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D013629:Tamoxifen; C016601:afimoxifene; D004815:Epidermal Growth Factor; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases; D006904:Hydroxymethylglutaryl-CoA Synthase; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt