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Short stretches of rare codons regulate translation of the transcription factor ZEB2 in cancer cells

Short stretches of rare codons regulate translation of the transcription factor ZEB2 in cancer cells
Short stretches of rare codons regulate translation of the transcription factor ZEB2 in cancer cells

Two proteins comprising the ZEB family of zinc finger transcription factors, ZEB1 and ZEB2, execute EMT programs in embryonic development and cancer. By studying regulation of their expression, we describe a novel mechanism that limits ZEB2 protein synthesis. A protein motif located at the border of the SMAD-binding domain of ZEB2 protein induces ribosomal pausing and compromises protein synthesis. The function of this protein motif is dependent on stretches of rare codons, Leu(UUA)-Gly(GGU)-Val(GUA). Incorporation of these triplets in the homologous region of ZEB1 does not affect protein translation. Our data suggest that rare codons have a regulatory role only if they are present within appropriate protein structures. We speculate that pools of transfer RNA available for protein translation impact on the configuration of epithelial mesenchymal transition pathways in tumor cells.

Amino Acid Motifs, Cell Line, Tumor, Codon, Epithelial-Mesenchymal Transition, Glycine, Humans, Leucine, Neoplasms, Protein Biosynthesis, RNA, Transfer, Gly, RNA, Transfer, Leu, RNA, Transfer, Val, Signal Transduction, Valine, Zinc Finger E-box Binding Homeobox 2, Zinc Finger E-box-Binding Homeobox 1, Journal Article
0950-9232
6640-6648
Wan Makhtar, W.R.
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Browne, G.
34c7ad18-bc99-4b1c-929b-5c03355fcda0
Karountzos, A.
7d08ff5a-9a1a-4181-942b-5d31f1befc91
Stevens, C.
22cc53c5-7eaa-4f00-9778-0e707f8b929e
Alghamdi, Y.
e98e3479-07cc-4408-a38c-3f1cfe51e5c5
Bottrill, A.R.
fd5eac4d-3490-44b1-8a22-14c9c9c262e0
Mistry, S.
9ed47077-6ce5-4a6e-b94a-04105e0be9ac
Smith, E.
bde95863-5248-4059-bbf4-f06531d4560a
Bushel, M.
b8025d9b-ac6e-43d4-b3ca-135a2526b3b9
Pringle, J.H.
56fcedc7-8f20-475d-9c9e-cd83cb2797ea
Sayan, A.E.
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077
Tulchinsky, E.
f0b81c60-c1cd-480b-936b-56bcd383e419
Wan Makhtar, W.R.
0d584a07-1f64-4f46-a8b1-5a905106ad24
Browne, G.
34c7ad18-bc99-4b1c-929b-5c03355fcda0
Karountzos, A.
7d08ff5a-9a1a-4181-942b-5d31f1befc91
Stevens, C.
22cc53c5-7eaa-4f00-9778-0e707f8b929e
Alghamdi, Y.
e98e3479-07cc-4408-a38c-3f1cfe51e5c5
Bottrill, A.R.
fd5eac4d-3490-44b1-8a22-14c9c9c262e0
Mistry, S.
9ed47077-6ce5-4a6e-b94a-04105e0be9ac
Smith, E.
bde95863-5248-4059-bbf4-f06531d4560a
Bushel, M.
b8025d9b-ac6e-43d4-b3ca-135a2526b3b9
Pringle, J.H.
56fcedc7-8f20-475d-9c9e-cd83cb2797ea
Sayan, A.E.
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077
Tulchinsky, E.
f0b81c60-c1cd-480b-936b-56bcd383e419

Wan Makhtar, W.R., Browne, G., Karountzos, A., Stevens, C., Alghamdi, Y., Bottrill, A.R., Mistry, S., Smith, E., Bushel, M., Pringle, J.H., Sayan, A.E. and Tulchinsky, E. (2017) Short stretches of rare codons regulate translation of the transcription factor ZEB2 in cancer cells. Oncogene, 36 (47), 6640-6648. (doi:10.1038/onc.2017.273).

Record type: Article

Abstract

Two proteins comprising the ZEB family of zinc finger transcription factors, ZEB1 and ZEB2, execute EMT programs in embryonic development and cancer. By studying regulation of their expression, we describe a novel mechanism that limits ZEB2 protein synthesis. A protein motif located at the border of the SMAD-binding domain of ZEB2 protein induces ribosomal pausing and compromises protein synthesis. The function of this protein motif is dependent on stretches of rare codons, Leu(UUA)-Gly(GGU)-Val(GUA). Incorporation of these triplets in the homologous region of ZEB1 does not affect protein translation. Our data suggest that rare codons have a regulatory role only if they are present within appropriate protein structures. We speculate that pools of transfer RNA available for protein translation impact on the configuration of epithelial mesenchymal transition pathways in tumor cells.

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Accepted/In Press date: 3 July 2017
e-pub ahead of print date: 7 August 2017
Published date: 23 November 2017
Keywords: Amino Acid Motifs, Cell Line, Tumor, Codon, Epithelial-Mesenchymal Transition, Glycine, Humans, Leucine, Neoplasms, Protein Biosynthesis, RNA, Transfer, Gly, RNA, Transfer, Leu, RNA, Transfer, Val, Signal Transduction, Valine, Zinc Finger E-box Binding Homeobox 2, Zinc Finger E-box-Binding Homeobox 1, Journal Article

Identifiers

Local EPrints ID: 417600
URI: http://eprints.soton.ac.uk/id/eprint/417600
ISSN: 0950-9232
PURE UUID: 1988e922-3e8d-46a9-85b3-be9ea965323a
ORCID for A.E. Sayan: ORCID iD orcid.org/0000-0002-5291-1485

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Date deposited: 07 Feb 2018 17:30
Last modified: 16 Mar 2024 04:04

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Contributors

Author: W.R. Wan Makhtar
Author: G. Browne
Author: A. Karountzos
Author: C. Stevens
Author: Y. Alghamdi
Author: A.R. Bottrill
Author: S. Mistry
Author: E. Smith
Author: M. Bushel
Author: J.H. Pringle
Author: A.E. Sayan ORCID iD
Author: E. Tulchinsky

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