Cited by 108RNA Research and SplicingGlioma Diagnosis and TreatmentCancer-related molecular mechanisms research

RNA-binding protein PCBP2 modulates glioma growth by regulating FHL3

Open access
Han, Wei, Xin, Zhongshuai, Zhao, Zhiqiang, Bao, Wen, Lin, Xihua, Yin, Bin, Zhao, Jizong, Yuan, Jiangang +2 more·2013·Journal of Clinical Investigation

Abstract

PCBP2 is a member of the poly(C)-binding protein (PCBP) family, which plays an important role in posttranscriptional and translational regulation by interacting with single-stranded poly(C) motifs in target mRNAs. Several PCBP family members have been reported to be involved in human malignancies. Here, we show that PCBP2 is upregulated in human glioma tissues and cell lines. Knockdown of PCBP2 inhibited glioma growth in vitro and in vivo through inhibition of cell-cycle progression and induction of caspase-3-mediated apoptosis. Thirty-five mRNAs were identified as putative PCBP2 targets/interactors using RIP-ChIP protein-RNA interaction arrays in a human glioma cell line, T98G. Four-and-a-half LIM domain 3 (FHL3) mRNA was downregulated in human gliomas and was identified as a PCBP2 target. Knockdown of PCBP2 enhanced the expression of FHL3 by stabilizing its mRNA. Overexpression of FHL3 attenuated cell growth and induced apoptosis. This study establishes a link between PCBP2 and FHL3 proteins and identifies a new pathway for regulating glioma progression.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1172/jci61820

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The direction of the influence of an RBP on the stability and translation efficiency of RNA can depend on the cell type and on the target RNA, as exemplified by PCBP2.

    “Nevertheless, it should be noted that the direction of the influence of an RBP on the stability and translation efficiency of RNA can depend on the cell type and on the target RNA, as exemplified by PCBP2: it can stabilize some mRNAs but promotes the degradation of other mRNAs [25,26,27].”

    From Untranslated Region Sequences and the Efficacy of mRNA Vaccines against Tuberculosis (2024) · cites this paper as [26]

    The results (section labeled “Conflict of interest”; page unavailable) show that PCBP2 knockdown prolonged FHL3 mRNA half-life in T98G glioma cells, supporting the claim that PCBP2 can promote degradation of a target mRNA. The paper also cites work on stabilization of other mRNAs, but its own experiments do not establish that the direction of PCBP2’s effect depends on cell type. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

No references could be resolved yet.

Research works printed but not linked: 45

  1. Makeyev AV, Liebhaber SA. The poly(C)-binding proteins: a multiplicity of functions and a search for mechanisms. RNA. 2002;8(3):265-278.
  2. Choi HS, Hwang CK, Song KY, Law PY, Wei LN, Loh HH. Poly(C)-binding proteins as transcrip- tional regulators of gene expression. Biochem Bio- phys Res Commun. 2009;380(3):431-436.
  3. Leffers H, Dejgaard K, Celis JE. Characterisation of two major cellular poly(rC)-binding human pro- teins, each containing three K-homologous (KH) domains. Eur J Biochem. 1995;230(2):447-453.
  4. Makeyev AV, Liebhaber SA. Identification of two novel mammalian genes establishes a subfamily of KH-domain RNA-binding proteins. Genomics. 2000;67(3):301-316.
  5. Ritchie SA, et al. Identification of the SRC pyrim- idine-binding protein (SPy) as hnRNP K: impli- cations in the regulation of SRC1A transcription. Nucleic Acids Res. 2003;31(5):1502-1513.
  6. Evans JR, et al. Members of the poly (rC) binding protein family stimulate the activity of the c-myc internal ribosome entry segment in vitro and in vivo. Oncogene. 2003;22(39):8012-2020.
  7. Pillai MR, Chacko P, Kesari LA, Jayaprakash PG, Jayaram HN, Antony AC. Expression of folate receptors and heterogeneous nuclear ribonucleo- protein E1 in women with human papillomavirus mediated transformation of cervical tissue to can- cer. J Clin Pathol. 2003;56(8):569-574.
  8. Thakur S, et al. Regulation of BRCA1 transcription by specific single-stranded DNA binding factors. Mol Cell Biol. 2003;23(11):3774-3787.
  9. Cloke B, et al. The poly(c)-binding protein-1 reg- ulates expression of the androgen receptor. Endo- crinology. 2010;151(8):3954-3964.
  10. Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH. TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol. 2010;12(3):286-293.
  11. Wang H, et al. PCBP1 suppresses the translation of metastasis-associated PRL-3 phosphatase. Cancer Cell. 2010;18(1):52-62.
  12. Tommerup N, Leffers H. Assignment of human KH-box-containing genes by in situ hybridization: HNRNPK maps to 9q21.32-q21.33, PCBP1 to 2p12-p13, and PCBP2 to 12q13.12-q13.13, distal to FRA12A. Genomics. 1996;32(2):297-298.
  13. Perrotti D, Calabretta B. Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA-binding proteins. Oncogene. 2002;21(56):8577-8583.
  14. Roychoudhury P, Paul RR, Chowdhury R, Chaud- huri K. HnRNP E2 is downregulated in human oral cancer cells and the overexpression of hnRNP E2 induces apoptosis. Mol Carcinog. 2007;46(3):198-207.
  15. Sean P, Nguyen JH, Semler BL. The linker domain of poly(rC) binding protein 2 is a major determi- nant in poliovirus cap-independent translation. Virology. 2008;378(2):243-253.
  16. Sean P, Nguyen JH, Semler BL. Altered interactions between stem-loop IV within the 5′ noncoding region of coxsackievirus RNA and poly(rC) bind- ing protein 2: effects on IRES-mediated translation and viral infectivity. Virology. 2009;389(1-2):45-58.
  17. Fukushi S, Okada M, Kageyama T, Hoshino FB, Nagai K, Katayama K. Interaction of poly(rC)-bind- ing protein 2 with the 5′-terminal stem loop of the hepatitis C-virus genome. Virus Res. 2001;73(1):67-79.
  18. Pan T, Fang C, Yi Z, Yang P, Yuan Z. Subproteomic analysis of the cellular proteins associated with the 3′ untranslated region of the hepatitis C virus genome in human liver cells. Biochem Biophys Res Commun. 2006;347(3):683-691.
  19. You F, et al. PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat Immunol. 2009;10(12):1300-1308.
  20. Molinaro RJ, Jha BK, Malathi K, Varambally S, Chinnaiyan AM, Silverman RH. Selection and clon- ing of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2′,5′-oligoade- nylate synthetase from prostate cancer cells. Nucleic Acids Res. 2006;34(22):6684-6695.
  21. Chang JS, et al. High levels of the BCR/ABL onco- protein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven mye- loid differentiation. Blood. 2007;110(3):994-1003.
  22. Eiring AM, et al. miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA transla- tion in leukemic blasts. Cell. 2010;140(5): 652-665.
  23. Ghosh D, Srivastava GP, Xu D, Schulz LC, Rob- erts RM. A link between SIN1 (MAPKAP1) and poly(rC) binding protein 2 (PCBP2) in counteract- ing environmental stress. Proc Natl Acad Sci U S A. 2008;105(33):11673-11678.
  24. Waggoner SA, Johannes GJ, Liebhaber SA. Deple- tion of the poly(C)-binding proteins alphaCP1 and alphaCP2 from K562 cells leads to p53-inde- pendent induction of cyclin-dependent kinase inhibitor (CDKN1A) and G1 arrest. J Biol Chem. 2009;284(14):9039-9049.
  25. Uchida H, et al. Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol Ther. 2004;10(1):162-171.
  26. Eiring AM, et al. Identification of novel posttran- scriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis. Blood. 2008;111(2):816-828.
  27. Waggoner SA, Liebhaber SA. Identification of mRNAs associated with alphaCP2-containing RNP complexes. Mol Cell Biol. 2003;23(19):7055-7067.
  28. de Sousa Abreu R, et al. Genomic analyses of musashi1 downstream targets show a strong asso- ciation with cancer-related processes. J Biol Chem. 2009;284(18):12125-12135.
  29. Chkheidze AN, Lyakhov DL, Makeyev AV, Morales J, Kong J, Liebhaber SA. Assembly of the alpha-glo- bin mRNA stability complex reflects binary inter- action between the pyrimidine-rich 3′ untranslated region determinant and poly(C) binding protein alphaCP. Mol Cell Biol. 1999;19(7):4572-4581.
  30. Kong J, Sumaroka M, Eastmond DL, Liebhaber SA. Shared stabilization functions of pyrimi- dine-rich determinants in the erythroid 15-lipox- ygenase and alpha-globin mRNAs. Mol Cell Biol. 2006;26(15):5603-5614.
  31. Ji X, Kong J, Liebhaber SA. In vivo association of the stability control protein alphaCP with actively trans- lating mRNAs. Mol Cell Biol. 2003;23(3):899-907.
  32. Du Z, Lee JK, Fenn S, Tjhen R, Stroud RM, James TL. X-ray crystallographic and NMR studies of pro- tein-protein and protein-nucleic acid interactions involving the KH domains from human poly(C)-bind- ing protein-2. RNA. 2007;13(7):1043-1051.
  33. Stefanovic B, Hellerbrand C, Holcik M, Briendl M, Aliebhaber S, Brenner DA. Posttranscriptional regulation of collagen alpha1(I) mRNA in hepatic stellate cells. Mol Cell Biol. 1997;17(9):5201-5209.
  34. Paulding WR, Czyzyk-Krzeska MF. Regula- tion of tyrosine hydroxylase mRNA stability by protein-binding, pyrimidine-rich sequence in the 3′-untranslated region. J Biol Chem. 1999; 274(4):2532-2538.
  35. Li M, et al. The four-and-a-half-LIM protein 2 (FHL2) is overexpressed in gliomas and associated with onco- genic activities. Glia. 2008;56(12):1328-1338.
  36. Morgan MJ, Whawell SA. The structure of the human LIM protein ACT gene and its expression in tumor cell lines. Biochem Biophys Res Commun. 2000;273(2):776-783.
  37. Johannessen M, Møller S, Hansen T, Moens U, Van Ghelue M. The multifunctional roles of the four- and-a-half-LIM only protein FHL2. Cell Mol Life Sci. 2006;63(3):268-284.
  38. Ding L, et al. Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway. J Clin Invest. 2009;119(2):349-361.
  39. Hubbi ME, Gilkes DM, Baek JH, Semenza GL. Four-and-a-half LIM domain proteins inhibit transactivation by hypoxia-inducible factor 1. J Biol Chem. 2012;287(9):6139-6149.
  40. Mils V, et al. LIM-only protein FHL3 inter- acts with CDC25B2 phosphatase. Exp Cell Res. 2003;285(1):99-106.
  41. Niu C, et al. Downregulation and antiprolifer- ative role of FHL3 in breast cancer. IUBMB Life. 2011;63(9):764-771.
  42. Xia W, et al. Identification and characterization of FHL3 as a novel angiogenin-binding partner. Gene. 2012;504(2):233-237.
  43. Zhang Y, et al. MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med. 2009;87(1):43-51.
  44. Penalva LO, Keene JD. Biotinylated tags for recov- ery and characterization of ribonucleoprotein com- plexes. Biotechniques. 2004;37(4):604-610.
  45. Teicher BA, Menon K, Alvarez E, Galbreath E, Shih C, Faul M. Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human T98G glioblastoma multiforme xenografts. Clin Cancer Res. 2001;7(3):634-640.

Cited by

Sorted by citations

Authors
Han, W., Xin, Z., Zhao, Z., Bao, W., Lin, X., Yin, B., Zhao, J., Yuan, J., Qiang, B., & Peng, X.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Beijing Tian Tan Hospital (CN)
Venue
Journal of Clinical Investigation
Published
2013-04-15
Volume
123
Issue
5
Pages
2103-2118
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2038520241
Cited by
108
References
0
Citations by year
2026: 4 · 2025: 5 · 2024: 6 · 2023: 9 · 2022: 7 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 9 · 2017: 6 · 2016: 9 · 2015: 16 · 2014: 11
FWCI
4.52
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Key Research and Development Program of China
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Keywords
PCBP2, FHL3, glioma, RNA-binding proteins, mRNA stabilization, post-transcriptional regulation, cell cycle progression, caspase-3, apoptosis, T98G cells, RIP-Chip, RNA-protein interactions, glioma progression
MeSH terms
Animals, Brain Neoplasms, Cell Cycle, Flow Cytometry, Glioma, Humans, Mice, Nude, Neoplasm Transplantation, Gene Expression Regulation, Neoplastic, RNA-Binding Proteins, Apoptosis, Disease Progression, Cell Line, Tumor, Chromatin Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Caspase 3, LIM Domain Proteins

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 ›

Are you an author, or do you see a problem with this page? Request a review