ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5′UTR
Open accessAbstract
p27 Kip1 restrains cell proliferation by binding to and inhibiting cyclin-dependent kinases. To investigate the mechanisms of p27 translational regulation, we isolated a complete p27 cDNA and identified an internal ribosomal entry site (IRES) located in its 5′UTR. The IRES allows for efficient p27 translation under conditions where cap-dependent translation is reduced. Searching for possible regulators of IRES activity we have identified the neuronal ELAV protein HuD as a specific binding factor of the p27 5′UTR. Increased expression of HuD or the ubiquitously expressed HuR protein specifically inhibits p27 translation and p27 IRES activity. Consistent with an inhibitory role of Hu proteins in p27 translation, siRNA mediated knockdown of HuR induced endogenous p27 protein levels as well as IRES-mediated reporter translation and leads to cell cycle arrest in G1.
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Translational silencing by HuD requires binding to an internal ribosome entry site (IRES) in the 5′ UTR of p27 mRNA and a short approximately 22-nt sequence in the 5′ UTR of Ins2 mRNA.
“Even though the mechanism of translational silencing is unclear, it was demonstrated to require HuD binding to an internal ribosome entry site (IRES) in the 5′ UTR of p27 mRNA (Kullmann et al. 2002) and a short ∼22-nt sequence in the 5′ UTR of Ins2 mRNA (Lee et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Kullmann et al. 2002
The Results (page not provided) show that HuD binds specifically to the p27 5′ UTR and that HuD overexpression inhibits p27 translation and IRES activity. They do not establish that HuD binds the IRES itself or that such binding is required for silencing. The Ins2 sequence is attributed to Lee et al. (2012), not to Kullmann et al. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHuD is capable of repressing protein synthesis, as shown for p27 and preproinsulin (Ins2) mRNAs.
“In addition to enhancing translation, HuD is capable of repressing protein synthesis, as shown for p27 and preproinsulin (Ins2) mRNAs (Kullmann et al. 2002; Lee et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Kullmann et al. 2002
Inhibition of p27 translation by Hu proteins is an event that sustains cells in a proliferative state.
“The report by Kullman et al. suggests that inhibition of p27 translation by Hu proteins is an event that sustains cells in a proliferative state (Kullmann et al. 2002).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Kullmann et al. 2002
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Research works printed but not linked: 2
- Pe'ery, T. and Mathews, M.B. 2000. Viral translational strate- gies and host defense mechanisms. In Translational control of gene expression (ed. M.B. Mathews), pp. 371-424. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
- Raught, B., Gingras, A.-C., and Sonenberg, N. 2000. Regulation of ribosomal recruitment in eukaryotes. In Translational control of gene expression (ed. M.B. Mathews), pp. 245-293.
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- Authors
- Kullmann, M., Göpfert, U., Siewe, B., & Hengst, L.
- Affiliations
- Max Planck Society (DE)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2002-12-01
- Volume
- 16
- Issue
- 23
- Pages
- 3087-3099
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC187493
- OpenAlex
- W2110062940
- Cited by
- 327
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 12 · 2021: 10 · 2020: 11 · 2019: 11 · 2018: 17 · 2017: 7 · 2016: 17 · 2015: 9 · 2014: 16 · 2013: 16 · 2012: 21
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- 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
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p27, HUD, HuR, internal ribosome entry site, 5' untranslated region, translational regulation, cap-independent translation, cell cycle arrest, G1 cell cycle arrest, cyclin-dependent kinase inhibition
- MeSH terms
- Base Sequence, Fibroblasts, Gene Expression Regulation, HeLa Cells, Humans, Molecular Sequence Data, Ribonucleoproteins, RNA-Binding Proteins, Sequence Analysis, DNA, Proliferating Cell Nuclear Antigen, 5' Untranslated Regions, ELAV Proteins
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