Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

Abstract

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-3b phosphorylation at Ser9, stabilization and nuclear localization of b-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.

Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression

“…28 Id1 has also been shown to enhance endothelial progenitor cell-driven angiogenesis in ovarian cancer, an effect mediated largely by the PI3K/AKT signaling pathway. 29,30 We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation; this is consistent with the decrease in PI3K/p110g phosphorylation induced by loss of Id1, and it contrasts with the transcriptional effects of Id1, which depend on its bHLH domain, a domain not required for its interaction with AKT1. Moreover, Id2 and Id3, which both have bHLH domains, do not bind AKT1, together indicating that Id1 regulates AKT signaling through mechanisms distinct from its transcriptional effects.…”

ID4: a new player in the cancer arena

“…(B) Id1 expression in breast cancer cells is induced by cyclooxygenase-2-derived prostaglandin E2 (promoting metastasis) while is repressed by KLF17 (a metastatic suppressor) [51,52]. Id1 expression may negatively regulate PTEN, leading to Akt activation, and drives tumor reinitiation during breast cancer metastasis [53][54][55][56]. (C) In endothelial progenitor cells Id1 and Id3 maintain the expression of FGFR1, MMP2, laminin 5 and alpha 6-beta 4 integrin [57], thereby enabling the mobilization of EPC from the bone marrow to the site of the tumor in response to circulating cytokines [17,18].…”

Constitutive overexpression of Id‐1 in mammary glands of transgenic mice results in precocious and increased formation of terminal end buds, enhanced alveologenesis, delayed involution

“…Li et al (2007a) first reported that Id-1 activates the PI3K/Akt pathway, leading to cellular proliferation in esophageal cancer cells. Further, we have demonstrated Id-1 activates the PI3K/Akt-mediated Wnt signaling pathway by PTEN inhibition in MCF-7 cells (Lee et al, 2009). In this study, this mechanism is also proven by an animal model.…”

“…As described above, we previously demonstrated that Id-1 plays a role as an activator of the PI3K/Akt pathway and its downstream effectors by PTEN inhibition that is associated with the regulation of cell cycle progression and cellular proliferation (Lee et al, 2009). In the present study, we examined other pathways including TGF-b, BMP-2, and RAR-b as well as FGF3, all of which are known to be regulators of mammary gland development via activation of the Wnt pathway, using RT-PCR (Fig.…”