Candidate tumor suppressor B-cell translocation gene 3 impedes neoplastic progression by suppression of AKT.

Y-C Cheng,H-Y Chiang,P-L Lai,T-Y Lin,P-H Chen,W-C Lin,M-J Hwang,S-Y Shieh,H-C Yang,C-S Suen

doi:10.1038/cddis.2014.550

Abstract

BTG3 (B-cell translocation gene 3) is a p53 target that also binds and inhibits E2F1. Although it connects two major growth-regulatory pathways functionally and is downregulated in human cancers, whether and how BTG3 acts as a tumor suppressor remain largely uncharacterized. Here we present evidence that BTG3 binds and suppresses AKT, a kinase frequently deregulated in cancers. BTG3 ablation results in increased AKT activity that phosphorylates and inhibits glycogen synthase kinase 3β. Consequently, we also observed elevated β-catenin/T-cell factor activity, upregulation of mesenchymal markers, and enhanced cell migration. Consistent with these findings, BTG3 overexpression suppressed tumor growth in mouse xenografts, and was associated with diminished AKT phosphorylation and reduced β-catenin in tissue specimens. Significantly, a short BTG3-derived peptide was identified, which recapitulates these effects in vitro and in cells. Thus, our study provides mechanistic insights into a previously unreported AKT inhibitory pathway downstream of p53. The identification of an AKT inhibitory peptide also unveils a new avenue for cancer therapeutics development.

Highlights

G1-to-S progression via the downregulation of cyclin D1 and cyclin E,3 whereas BTG3 binds and inhibits E2F1, a transcription factor important for S-phase entry.[4]
BTG3 is a member of the B-cell translocation gene/transducer of ErbB2 (BTG/Tob) antiproliferative protein family that includes BTG1, BTG2/PC3/Tis[21] (TPA-induced sequence 21), BTG4, Tob[1], and Tob2.1 The members of this protein family are characterized by a conserved N-terminal domain containing box A and box B signature motifs, and a variable C-terminal domain.[2]
The activation of AKT requires the phosphorylation of its Thr[308] and Ser[473] residues by PDK1 and mTORC2, respectively,[20,21] which is mediated by the binding of the N-terminal pleckstrin homology (PH) domain to membrane phosphatidylinositol-3,4,5-trisphosphate

Summary

Introduction

G1-to-S progression via the downregulation of cyclin D1 and cyclin E,3 whereas BTG3 binds and inhibits E2F1, a transcription factor important for S-phase entry.[4]. AKT is involved in the regulation of many cellular processes via various downstream effectors such as mammalian target of the rapamycin (mTOR) in protein synthesis[15] and the transcription factors nuclear factor- κB and FOXO (forkhead box O) in cell survival.[16,17] Importantly, it allows the stabilization and subsequent nuclear localization of β-catenin by phosphorylating and inhibiting glycogen synthase kinase 3β (GSK3β), connecting β-catenin with cell growth and migration.[18,19] The activation of AKT requires the phosphorylation of its Thr[308] and Ser[473] residues by PDK1 (phosphoinositide-dependent kinase-1) and mTORC2 (mammalian target of rapamycin complex 2), respectively,[20,21] which is mediated by the binding of the N-terminal pleckstrin homology (PH) domain to membrane phosphatidylinositol-3,4,5-trisphosphate Upstream stimuli such as growth factors activate receptor tyrosine kinase, which triggers the activation of phosphoinositide 3-kinase (PI3K) and leads to the generation of PIP3. We delineated further the effects of the loss of BTG3 and demonstrated its role in safeguarding the AKT-GSK3β pathway, and, by crosstalk with the Wnt/β-catenin pathway, its role as a barrier to tumor progression

Methods

Results

Conclusion