Id-1 activates Akt-mediated Wnt signaling and p27kip1 phosphorylation through PTEN inhibition

Abstract

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 is a novel PTEN inhibitor and activates the Akt pathway via inhibition of 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 ChIP assay, the binding of p53 to 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 Akt-mediated canonical Wnt signaling pathway. The GSK-3b phosphorylation at Ser9, stabilization and nuclear localization of b-catenin, TCF/LEF transactivation activity and Cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27Kip1 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 Akt pathway and its downstream effectors, Wnt/TCF pathway and p27Kip1 phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.