Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins.
The P3k oncoprotein [homolog of the catalytic subunit p110alpha of class 1A phosphoinositide 3-kinase (PI3K)] and its downstream effector Akt induce oncogenic transformation in cultures of chicken embryo fibroblasts (CEF). The winged helix transcription factor FoxO1 is a growth-attenuating and proapoptotic protein and serves as a substrate of Akt. Here we show that FoxO1 expression is constitutively suppressed in CEF transformed by P3k or Akt. The FoxO1 protein level is high in serum-starved normal CEF, but platelet-derived growth factor treatment induces rapid phosphorylation and disappearance of FoxO1. PI3K inhibitors or the proteasome inhibitor lactacystin interfere with this process. These data suggest that phosphorylation-dependent degradation of FoxO1 by means of proteasomes plays a role in oncogenic transformation by P3k and Akt. A dominant negative mutant of FoxO1 containing the repressor domain of the Drosophila Engrailed protein induces partial oncogenic transformation of CEF and interferes with FoxO1-dependent transcriptional activation. The FoxG1 oncoprotein also inhibits transcriptional activation by FoxO1. Inhibition of FoxO1, albeit by different mechanisms, appears to be a common denominator of the PI3K and FoxG1 oncogenic pathways.
Aoki
Masahiro
M
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. maoki@mfour.med.kyoto-u.ac.jp
Jiang
Hao
H
Vogt
Peter K
PK
D000818:Animals; D002455:Cell Division; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002645:Chickens; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009097:Multienzyme Complexes; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C085126:FOXO1 protein, human; C494918:AKT1 protein, human