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Review
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Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions

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Review

Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions

Sachiko Matsuhashi et al. Int J Mol Sci.

Abstract

PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFβTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21.

Keywords: EGF; PDCD4; TPA; carcinogenesis; tumor promotor; tumor suppressor.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding this publication.

Figures

Figure 1
Figure 1
PDCD4, a tumor suppressor, suppresses carcinogenesis by multifunction.
Figure 2
Figure 2
Schematic structure of PDCD4-protein. NLS, Nuclear localization signal; RNA, RNA binding site; PABP, poly(A) binding protein (PABP) binding site; MA3, MA3 domain homologous to eIF4G M1 domain. PDCD4 protein interacts with eIF4A through the MA3 domain and inhibits cap-dependent protein synthesis.
Figure 3
Figure 3
Controls of translation by PDCD4. PDCD4 binds to eIF4A and inhibits its helicase activity suppressing the protein synthesis. Also, PDCD4 binds to the special secondary structure of mRNA and inhibits the protein synthesis.
Figure 4
Figure 4
Pathways of EGF mediated protein synthesis and PDCD4 degradation. EGF stimulates the phosphorylation of the eIF4E inhibitor 4E-BP via activation of PI3K-Akt-mTOR pathway and thereby activating protein synthesis. On the other hand, mTOR-activated S6K1 phosphorylates PDCD4-protein. The phosphorylated protein is ubiquitinated by SCFβTRCP (βTRCP) ubiquitin (Ubi) ligase and degraded in proteasomes stimulating protein synthesis.
Figure 5
Figure 5
Expression patterns of PDCD4 mutants in the presence or absence of inhibitors with or without tumor promoters. Huh7 cells transfected with the mutant PDCD4-GFP plasmids were treated with or without EGF or TPA in the presence or absence of rapamycin or pan-PKC inhibitor (pan-PKCI). The expression of ectopic mutant PDCD4 conjugated with GFP was analyzed by Western blot.
Figure 6
Figure 6
S6K1 phosphorylation sites and β-TRCP binding motif in the PDCD4 protein. (A) Serines (S) phosphorylated by S6K1 are marked with circles and SCFβTRCP binding sequence is underlined in the PDCD4 protein sequence. RXRXXS, Canonical S6K1 substrate consensus sequence. (B) Homology of the amino acid sequence around the three S6K1 phosphorylation sites in the PDCD4 protein.
Figure 7
Figure 7
EGF and TPA mediated pathway to phosphorylate serines in the SCFβTRCP recognition site of PDCD4-protein in Huh7 hepatoma cells. EGF activates PI3K-Akt-mTOR-S6K1 signaling pathway and the activated S6K1 phosphorylates PDCD4-protein at S67 and S76. TPA-mediated pathway via PKC-δ and/or PKC-ε may phosphorylate S71 and S76. PKC-dependent activation of S6K1 was not observed in Huh7 hepatoma cells.
Figure 8
Figure 8
PDCD4 expression is suppressed by miR21 via NF-κB and/or STAT3 in the cells in the inflammatory area.

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