A novel mechanism for the control of translation of specific mRNAs by tumor suppressor protein Pdcd4: Inhibition of translation elongation

Biyanee, A; Ohnheiser, J; Singh, P; Klempnauer, K-H

doi:10.1038/onc.2014.83

Cited by 37RNA and protein synthesis mechanismsRNA Research and SplicingPI3K/AKT/mTOR signaling in cancer

A novel mechanism for the control of translation of specific mRNAs by tumor suppressor protein Pdcd4: Inhibition of translation elongation

Biyanee, A, Ohnheiser, J, Singh, P, Klempnauer, K-H·2015·Oncogene

DOI 10.1038/onc.2014.83

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Abstract

The tumor suppressor gene Pdcd4 (programmed cell death gene 4) has drawn considerable attention because its downregulation is involved in the development of several types of cancer. Because Pdcd4 interacts with the translation initiation factor eIF4A and inhibits its helicase activity, Pdcd4 has been implicated in the translational suppression of cellular mRNAs containing structured 5'-untranslated regions. However, Pdcd4's role in translation regulation is still poorly understood, because only very few physiological Pdcd4 target mRNAs are known. By using a Pdcd4-deficient clone of the chicken B-cell line DT40, we have discovered that the mRNA of the A-myb proto-oncogene is a novel Pdcd4 target RNA whose translation is suppressed by Pdcd4. Interestingly, the inhibitory effect of Pdcd4 is independent of the Pdcd4-eIF4A interaction, but is dependent on an RNA-binding domain at the N terminus of Pdcd4 and on sequences located within the coding region of A-myb mRNA, indicating that Pdcd4 suppresses A-myb translation by a novel mechanism. Our data show that the Pdcd4 RNA-binding domain preferentially recognizes an RNA secondary structure element formed by the part of the A-myb coding region that mediates Pdcd4-dependent suppression. Previously, we have shown that Pdcd4 also suppresses the translation of the c-myb mRNA by a similar mechanism involving binding of Pdcd4 to RNA secondary structure formed by the c-myb coding region. Surprisingly, our data show that Pdcd4 exerts its inhibitory activity only when the target region of Pdcd4 in A-myb and c-myb mRNA is itself translated, consistent with a mechanism in which Pdcd4 suppresses translation by interfering with translation elongation. Taken together, our work reveals a novel mechanism by which Pdcd4 affects the translational of cellular RNAs. Furthermore, as c-myb and A-myb are members of the Myb proto-oncogene family whose deregulation has been implicated in tumorigenesis, inhibiting their translation might contribute to the tumor-suppressive activity of Pdcd4.

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PDCD4 protein interacts with the coding region of c-Myb and A-Myb mRNA through the RNA binding domain and inhibits translation of the mRNA.
“It was shown that PDCD4-protein interacts with the coding region of c-Myb and A-Myb mRNA through the RNA binding domain and inhibits the translation of the mRNA [28,29].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [29]

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Abstract 3190: Inhibition of the translation of A-myb mRNA by tumor suppressor protein Pdcd4.
Biyanee, A., & Klempnauer, K. (2013) · Cancer Research · doi:10.1158/1538-7445.am2013-3190
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Pdcd4 directly binds the coding region of c-myb mRNA and suppresses its translation
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An evolutionarily conserved interaction of tumor suppressor protein Pdcd4 with the poly(A)-binding protein contributes to translation suppression by Pdcd4
Fehler, O., Singh, P., Haas, A., Ulrich, D., Müller, J. P., Ohnheiser, J., & Klempnauer, K.-H. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku800 · Cited by 35 · see citing works
Self-citation
Tumor Suppressor Protein Pdcd4 Inhibits Translation of p53 mRNA
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Self-citation

Authors: Biyanee, A., Ohnheiser, J., Singh, P., & Klempnauer, K.-H.
Affiliations: University of Münster (DE)
Corresponding author: Klempnauer, K-H
ORCID: Biyanee, A
Singh, P
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2014-03-31
Volume: 34
Issue: 11
Pages: 1384-1392
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/onc.2014.83
OpenAlex: W2077802216
Cited by: 37
References: 58
Citations by year: 2026: 1 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 6 · 2014: 4
FWCI: 2.19
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft
Deutsche Krebshilfe
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: PDCD4, A-MYB, MYB, RNA-binding domain, RNA secondary structure, protein synthesis inhibition, tumor suppressor, DT40 B cells
MeSH terms: Animals, Chickens, Peptide Chain Elongation, Translational, Proto-Oncogene Proteins, Quail, RNA, Messenger, Trans-Activators, RNA-Binding Proteins, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myb, Tumor Suppressor Proteins, Avian Proteins, Eukaryotic Initiation Factor-4A, Cell Line, Tumor, Apoptosis Regulatory Proteins, Gene Knockout Techniques, Carcinogenesis

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A novel mechanism for the control of translation of specific mRNAs by tumor suppressor protein Pdcd4: Inhibition of translation elongation

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