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Cited by 114RNA Research and SplicingRNA regulation and diseaseRNA and protein synthesis mechanisms

A Nuclear Function of Hu Proteins as Neuron-specific Alternative RNA Processing Regulators

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Zhu, Hui, Hasman, Robert A., Barron, Victoria A., Luo, Guangbin, Lou, Hua·2006·Molecular Biology of the Cell
DOI 10.1091/mbc.e06-02-0099PMC PMC1679676
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Abstract

Recent advances in genome-wide analysis of alternative splicing indicate that extensive alternative RNA processing is associated with many proteins that play important roles in the nervous system. Although differential splicing and polyadenylation make significant contributions to the complexity of the nervous system, our understanding of the regulatory mechanisms underlying the neuron-specific pathways is very limited. Mammalian neuron-specific embryonic lethal abnormal visual-like Hu proteins (HuB, HuC, and HuD) are a family of RNA-binding proteins implicated in neuronal differentiation and maintenance. It has been established that Hu proteins increase expression of proteins associated with neuronal function by up-regulating mRNA stability and/or translation in the cytoplasm. We report here a novel function of these proteins as RNA processing regulators in the nucleus. We further elucidate the underlying mechanism of this regulation. We show that in neuron-like cells, Hu proteins block the activity of TIA-1/TIAR, two previously identified, ubiquitously expressed proteins that promote the nonneuronal pathway of calcitonin/calcitonin gene-related peptide (CGRP) pre-mRNA processing. These studies define not only the first neuron-specific regulator of the calcitonin/CGRP system but also the first nuclear function of Hu proteins.

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  • Hu proteins bind U-rich sequences downstream from the exon 4 poly(A) signal in calcitonin/CGRP to block binding of CstF64 and CPSF, preventing cleavage and polyadenylation at the nonneuronal exon 4 poly(A) signal and thereby promoting the neuron-specific CGRP pathway.

    “Employing mainly REMSAs and in vitro cleavage and polyadenylation assays, one study determined that Hu proteins bind U-rich sequences downstream from the exon 4 poly(A) signal in calcitonin/CGRP to block binding of cleavage stimulation factor 64 (CstF64) and cleavage-polyadenylation specificity factor (CPSF), essential components of the cleavage and polyadenylation machinery. Through this”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Zhu et al. 2006

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  • All three RRMs are necessary for Hu proteins to perform alternative polyadenylation.

    “Truncation of the mouse HuB protein revealed that all three RRMs are necessary for Hu proteins to perform this function (Zhu et al. 2006).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Zhu et al. 2006

    The Results report that Hu proteins regulate alternative processing of calcitonin/CGRP RNA and that a mouse HuC construct containing RRM3 and the hinge domain disrupted CGRP production, whereas an RRM1–RRM2 construct did not significantly affect exon inclusion. These experiments do not establish that all three RRMs are necessary for alternative polyadenylation, and the tested truncations were of mouse HuC, not mouse HuB. The cited copy provides no page numbers for these passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • nELAVs compete with TIA-1/TIAR RBPs for a U-rich intronic sequence in the calcitonin/calcitonin gene-related peptide (CGRP) pre-mRNA to block inclusion of exon 4, thereby promoting expression of the neuron-specific CGRP isoform in neurons.

    “Using various complementary methods, such as REMSA and UV cross-linking/IP assays, one report demonstrated that nELAVs compete with TIA-1/TIAR RBPs for a U-rich intronic sequence in the calcitonin/calcitonin gene-related peptide (CGRP) pre-mRNA to block inclusion of exon 4. Through this mechanism, nELAVs promote expression of the neuron-specific CGRP isoform in neurons (Zhu et al. 2006).”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Zhu et al. 2006

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Cited by

Sorted by citations

Authors
Zhu, H., Hasman, R. A., Barron, V. A., Luo, G., & Lou, H.
Affiliations
  • Case Western Reserve University (US)
  • Case Comprehensive Cancer Center (US)
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2006-12
Volume
17
Issue
12
Pages
5105-5114
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e06-02-0099
PMC
PMC1679676
OpenAlex
W2110141158
Cited by
114
References
4
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FWCI
3.67
Type
journal article
Language
en
Open access
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (0237685)
  • American Heart Association
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R56NS049103, R01NS049103, NS 049103-01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
HU protein, alternative splicing, alternative RNA processing, TIA-1, TIAR, calcitonin, calcitonin gene-related peptide, pre-mRNA processing, nuclear RNA-binding proteins, mRNA stability, neuronal differentiation
MeSH terms
T-Cell Intracellular Antigen-1, Animals, Base Sequence, Calcitonin, Cell Nucleus, Cricetulus, Enhancer Elements, Genetic, Exons, Cricetinae, HeLa Cells, Humans, Introns, Molecular Sequence Data, Neurons, Organ Specificity, Protein Binding, RNA Precursors, Uridine, Calcitonin Gene-Related Peptide, CHO Cells, RNA-Binding Proteins, Alternative Splicing, Poly(A)-Binding Proteins, Mice, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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