Id-1 activates Akt-mediated Wnt signaling and p27(Kip1) phosphorylation through PTEN inhibition.
Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3beta phosphorylation at Ser9, stabilization and nuclear localization of beta-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27(Kip1) phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27(Kip1) phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.
Lee
J-Y
JY
Department of Pathology, College of Medicine, Hanyang University, Seongdong-Gu, Seoul, Republic of Korea.
Kang
M-B
MB
Jang
S-H
SH
Qian
T
T
Kim
H-J
HJ
Kim
C-H
CH
Kim
Y
Y
Kong
G
G
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013347:Subcellular Fractions; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human