IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a.
Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival. We investigated the pathological relationship between phosphoylated-Akt (Akt-p) and FOXO3a in primary tumors. Surprisingly, FOXO3a was found to be excluded from the nuclei of some tumors lacking Akt-p, suggesting an Akt-independent mechanism of regulating FOXO3a localization. We provide evidence for such a mechanism by showing that IkappaB kinase (IKK) physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXO3a via the Ub-dependent proteasome pathway. Cytoplasmic FOXO3a correlates with expression of IKKbeta or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKbeta promotes cell proliferation and tumorigenesis that can be overridden by FOXO3a. These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis.
Hu
Mickey C-T
MC
Department of Molecular and Cellular Oncology, The University of Texas, Houston, TX 77030, USA. michu@mdanderson.org
Lee
Dung-Fang
DF
Xia
Weiya
W
Golfman
Leonard S
LS
Ou-Yang
Fu
F
Yang
Jer-Yen
JY
Zou
Yiyu
Y
Bao
Shilai
S
Hanada
Norihisa
N
Saso
Hitomi
H
Kobayashi
Ryuji
R
Hung
Mien-Chie
MC
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase; D051379:Mice; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; 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 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex