Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins

M Aoki, H Jiang, PK Vogt - Proceedings of the National …, 2004 - National Acad Sciences
M Aoki, H Jiang, PK Vogt
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
The P3k oncoprotein [homolog of the catalytic subunit p110α 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 …
The P3k oncoprotein [homolog of the catalytic subunit p110α 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.
National Acad Sciences