Enhanced Arginine Methylation of Programmed Cell Death 4 Protein during Nutrient Deprivation Promotes Tumor Cell Viability
Open accessAbstract
The role of programmed cell death 4 (PDCD4) in tumor biology is context-dependent. PDCD4 is described as a tumor suppressor, but its coexpression with protein arginine methyltransferase 5 (PRMT5) promotes accelerated tumor growth. Here, we report that PDCD4 is methylated during nutrient deprivation. Methylation occurs because of increased stability of PDCD4 protein as well as increased activity of PRMT5 toward PDCD4. During nutrient deprivation, levels of methylated PDCD4 promote cell viability, which is dependent on an enhanced interaction with eIF4A. Upon recovery from nutrient deprivation, levels of methylated PDCD4 are regulated by phosphorylation, which controls both the localization and stability of methylated PDCD4. This study reveals that, in response to particular environmental cues, the role of PDCD4 is up-regulated and is advantageous for cell viability. These findings suggest that the methylated form of PDCD4 promotes tumor viability during nutrient deprivation, ultimately allowing the tumor to grow more aggressively.
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.
Integrity signals
Registry
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.
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?
Methylation of PDCD4 at 110R by PRMT5 increased PDCD4 levels, tumor cell growth, and viability in a nutritional deprivation condition.
“It was shown that the methylation of PDCD4 at 110R by arginine methyltransferase 5 (PRMT5) increased the PDCD4 levels, tumor cell growth and viability in a nutritional deprivation condition [64].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [64]
The Results (page not provided) report greater viability during nutrient deprivation in MCF7 cells expressing PDCD4 and PRMT5 than in cells expressing the R110K mutant. The Abstract and Results describe increased PDCD4 stability as a cause of increased methylation, not an effect of methylation. The Discussion presents enhanced tumor growth as a proposed consequence, rather than a growth outcome measured under nutrient deprivation in this study. (LLM, conf=0.88)
Experimental — accuracy not yet measuredArginine methylation may inhibit PDCD4 protein functions and allow the tumor to grow more aggressively.
“The arginine methylation may inhibit PDCD4-protein functions and allow the tumor to grow more aggressively.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [64]
The Abstract and Discussion link methylated PDCD4 to greater tumor-cell viability and suggest an advantage for tumor growth. But the claim that methylation inhibits PDCD4 function is not supported: the Results report that methylation enhances PDCD4’s interaction with eIF4A, and the Discussion describes its role as context-dependent. (LLM, conf=0.88)
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
Tumor suppressors and cell metabolism: a recipe for cancer growth
Jones, R. G., & Thompson, C. B. (2009) · Genes & Development · doi:10.1101/gad.1756509 · Cited by 1,085 · see citing works
Yang, H.-S., Jansen, A. P., Komar, A. A., Zheng, X., Merrick, W. C., Costes, S., Lockett, S. J., Sonenberg, N., & Colburn, N. H. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.26-37.2003 · Cited by 494 · see citing works
Yang, H.-S., Matthews, C. P., Clair, T., Wang, Q., Baker, A. R., Li, C.-C. H., Tan, T.-H., & Colburn, N. H. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.4.1297-1306.2006 · Cited by 202 · see citing works
PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains
Suzuki, C., Garces, R. G., Edmonds, K. A., Hiller, S., Hyberts, S. G., Marintchev, A., & Wagner, G. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712235105 · Cited by 165 · see citing works
Leupold, J. H., Yang, H.-S., Colburn, N. H., Asangani, I., Post, S., & Allgayer, H. (2007) · Oncogene · doi:10.1038/sj.onc.1210234 · Cited by 163 · see citing works
Translation Inhibitor Pdcd4 Is Targeted for Degradation during Tumor Promotion
Schmid, T., Jansen, A. P., Baker, A. R., Hegamyer, G., Hagan, J. P., & Colburn, N. H. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-1719 · Cited by 151 · see citing works
Akt Phosphorylates and Regulates Pdcd4 Tumor Suppressor Protein
Palamarchuk, A., Efanov, A., Maximov, V., Aqeilan, R. I., Croce, C. M., & Pekarsky, Y. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-3469 · Cited by 151 · see citing works
Bitomsky, N., Böhm, M., & Klempnauer, K.-H. (2004) · Oncogene · doi:10.1038/sj.onc.1208064 · Cited by 134 · see citing works
Crystal structure of the eIF4A–PDCD4 complex
Chang, J. H., Cho, Y. H., Sohn, S. Y., Choi, J. M., Kim, A., Kim, Y. C., Jang, S. K., & Cho, Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808275106 · Cited by 120 · see citing works
The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA
Böhm, M., Sawicka, K., Siebrasse, J. P., Brehmer-Fastnacht, A., Peters, R., & Klempnauer, K.-H. (2003) · Oncogene · doi:10.1038/sj.onc.1206710 · Cited by 101 · see citing works
Kumar, N., Wethkamp, N., Waters, L. C., Carr, M. D., & Klempnauer, K.-H. (2013) · Oncogenesis · doi:10.1038/oncsis.2012.37 · Cited by 30 · see citing works
Regulation of tumor suppressor PDCD4 by novel protein kinase C isoforms
Nakashima, M., Hamajima, H., Xia, J., Iwane, S., Kwaguchi, Y., Eguchi, Y., Mizuta, T., Fujimoto, K., Ozaki, I., & Matsuhashi, S. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.05.002 · Cited by 17 · see citing works
Flagged first, then by citations
Research works printed but not linked: 39
- [1]1. Mudduluru, G. ∙ Medved, F. ∙ Grobholz, R. ... Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer Cancer. 2007; 110:1697-1707 Crossref Scopus (184) PubMed Google Scholar
- [2]2. Gao, F. ∙ Wang, X. ∙ Zhu, F. ... PDCD4 gene silencing in gliomas is associated with 5′CpG island methylation and unfavourable prognosis J. Cell. Mol. Med. 2009; 13:4257-4267 Crossref Scopus (57) PubMed Google Scholar
- [3]3. Wang, X. ∙ Wei, Z. ∙ Gao, F. ... Expression and prognostic significance of PDCD4 in human epithelial ovarian carcinoma Anticancer Res. 2008; 28:2991-2996 PubMed Google Scholar
- [4]4. Fassan, M. ∙ Cagol, M. ∙ Pennelli, G. ... Programmed cell death 4 protein in esophageal cancer Oncol. Rep. 2010; 24:135-139 PubMed Google Scholar
- [5]5. Powers, M.A. ∙ Fay, M.M. ∙ Factor, R.E. ... Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4 Cancer Res. 2011; 71:5579-5587 Crossref Scopus (120) PubMed Google Scholar
- [7]7. Santhanam, A.N. ∙ Baker, A.R. ∙ Hegamyer, G. ... Pdcd4 repression of lysyl oxidase inhibits hypoxia-induced breast cancer cell invasion Oncogene. 2010; 29:3921-3932 Crossref Scopus (60) PubMed Google Scholar
- [8]8. Wang, Q. ∙ Sun, Z. ∙ Yang, H.S. Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both β-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells Oncogene. 2008; 27:1527-1535 Crossref Scopus (142) PubMed Google Scholar
- [10]10. Yang, H.S. ∙ Knies, J.L. ∙ Stark, C. ... Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation Oncogene. 2003; 22:3712-3720 Crossref Scopus (150) PubMed Google Scholar
- [11]11. Cmarik, J.L. ∙ Min, H. ∙ Hegamyer, G. ... Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation Proc. Natl. Acad. Sci. U.S.A. 1999; 96:14037-14042 Crossref Scopus (246) PubMed Google Scholar
- [12]12. Hilliard, A. ∙ Hilliard, B. ∙ Zheng, S.J. ... Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4 J. Immunol. 2006; 177:8095-8102 Crossref Scopus (154) PubMed Google Scholar
- [13]13. Jansen, A.P. ∙ Camalier, C.E. ∙ Colburn, N.H. Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis Cancer Res. 2005; 65:6034-6041 Crossref Scopus (207) PubMed Google Scholar
- [14]14. Yang, H.S. ∙ Cho, M.H. ∙ Zakowicz, H. ... A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A Mol. Cell. Biol. 2004; 24:3894-3906 Crossref Scopus (185) PubMed Google Scholar
- [15]15. Waters, L.C. ∙ Veverka, V. ∙ Böhm, M. ... Structure of the C-terminal MA-3 domain of the tumour suppressor protein Pdcd4 and characterization of its interaction with eIF4A Oncogene. 2007; 26:4941-4950 Crossref Scopus (47) PubMed Google Scholar
- [16]16. Waters, L.C. ∙ Strong, S.L. ∙ Ferlemann, E. ... Structure of the tandem MA-3 region of Pdcd4 protein and characterization of its interactions with eIF4A and eIF4G: molecular mechanisms of a tumor suppressor J. Biol. Chem. 2011; 286:17270-17280 Full Text Full Text (PDF) Scopus (32) PubMed Google Scholar
- [17]17. Loh, P.G. ∙ Yang, H.S. ∙ Walsh, M.A. ... Structural basis for translational inhibition by the tumour suppressor Pdcd4 EMBO J. 2009; 28:274-285 Crossref Scopus (110) PubMed Google Scholar
- [18]18. LaRonde-LeBlanc, N. ∙ Santhanam, A.N. ∙ Baker, A.R. ... Structural basis for inhibition of translation by the tumor suppressor Pdcd4 Mol. Cell. Biol. 2007; 27:147-156 Crossref Scopus (67) PubMed Google Scholar
- [21]21. Dorrello, N.V. ∙ Peschiaroli, A. ∙ Guardavaccaro, D. ... S6K1- and βTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth Science. 2006; 314:467-471 Crossref Scopus (608) PubMed Google Scholar
- [24]24. Zoncu, R. ∙ Efeyan, A. ∙ Sabatini, D.M. mTOR: from growth signal integration to cancer, diabetes and ageing Nat. Rev. Mol. Cell Biol. 2011; 12:21-35 Crossref Scopus (3365) PubMed Google Scholar
- [25]25. Silvera, D. ∙ Formenti, S.C. ∙ Schneider, R.J. Translational control in cancer Nat. Rev. Cancer. 2010; 10:254-266 Crossref Scopus (670) PubMed Google Scholar
- [26]26. Ramírez-Valle, F. ∙ Badura, M.L. ∙ Braunstein, S. ... Mitotic raptor promotes mTORC1 activity, G2/M cell cycle progression, and internal ribosome entry site-mediated mRNA translation Mol. Cell. Biol. 2010; 30:3151-3164 Crossref Scopus (85) PubMed Google Scholar
- [28]28. Bedford, M.T. ∙ Clarke, S.G. Protein arginine methylation in mammals: who, what, and why Mol. Cell. 2009; 33:1-13 Full Text Full Text (PDF) Scopus (1398) PubMed Google Scholar
- [29]29. Rual, J.F. ∙ Hirozane-Kishikawa, T. ∙ Hao, T. ... Human ORFeome version 1.1: a platform for reverse proteomics Genome Res. 2004; 14:2128-2135 Crossref Scopus (196) PubMed Google Scholar
- [30]30. Bachand, F. Protein arginine methyltransferases: from unicellular eukaryotes to humans Eukaryot. Cell. 2007; 6:889-898 Crossref Scopus (101) PubMed Google Scholar
- [31]31. Hay, N. ∙ Sonenberg, N. Upstream and downstream of mTOR Genes Dev. 2004; 18:1926-1945 Crossref Scopus (3620) PubMed Google Scholar
- [32]32. Vaupel, P. Tumor microenvironmental physiology and its implications for radiation oncology Semin. Radiat. Oncol. 2004; 14:198-206 Crossref Scopus (794) PubMed Google Scholar
- [35]35. Waters, L.C. ∙ Oka, O. ∙ Muskett, F.W. ... Resonance assignment and secondary structure of the middle MA-3 domain and complete tandem MA-3 region of the tumour suppressor protein Pdcd4 Biomol. NMR Assign. 2010; 4:49-53 Crossref Scopus (2) PubMed Google Scholar
- [36]36. Hanahan, D. ∙ Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis Cell. 1996; 86:353-364 Full Text Full Text (PDF) Scopus (6257) PubMed Google Scholar
- [37]37. Kinoshita, E. ∙ Kinoshita-Kikuta, E. ∙ Takiyama, K. ... Phosphate-binding tag, a new tool to visualize phosphorylated proteins Mol. Cell. Proteomics. 2006; 5:749-757 Full Text Full Text (PDF) Scopus (890) PubMed Google Scholar
- [38]38. Asangani, I.A. ∙ Rasheed, S.A. ∙ Nikolova, D.A. ... MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer Oncogene. 2008; 27:2128-2136 Crossref Scopus (1663) PubMed Google Scholar
- [39]39. Lu, Z. ∙ Liu, M. ∙ Stribinskis, V. ... MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene Oncogene. 2008; 27:4373-4379 Crossref Scopus (654) PubMed Google Scholar
- [40]40. Frankel, L.B. ∙ Christoffersen, N.R. ∙ Jacobsen, A. ... Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells J. Biol. Chem. 2008; 283:1026-1033 Full Text Full Text (PDF) Scopus (1029) PubMed Google Scholar
- [41]41. Zhu, S. ∙ Wu, H. ∙ Wu, F. ... Micro RNA-21 targets tumor suppressor genes in invasion and metastasis Cell Res. 2008; 18:350-359 Crossref Scopus (1025) PubMed Google Scholar
- [42]42. Göke, R. ∙ Barth, P. ∙ Schmidt, A. ... Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21(Waf1/Cip1) Am. J. Physiol. Cell Physiol. 2004; 287:C1541-C1546 Crossref Scopus (133) PubMed Google Scholar
- [43]43. Olson, C.M. ∙ Donovan, M.R. ∙ Spellberg, M.J. ... The insulin receptor cellular IRES confers resistance to eIF4A inhibition eLife. 2013; 2:e00542 Crossref Scopus (28) PubMed Google Scholar
- [44]44. Kakade, D. ∙ Islam, N. ∙ Maeda, N. ... Differential effects of PDCD4 depletion on protein synthesis in myoblast and myotubes BMC Cell Biol. 2014; 15:2 Crossref Scopus (6) PubMed Google Scholar
- [45]45. Song, X. ∙ Zhang, X. ∙ Wang, X. ... Tumor suppressor gene PDCD4 negatively regulates autophagy by inhibiting the expression of autophagy-related gene ATG5 Autophagy. 2013; 9:743-755 Crossref Scopus (41) PubMed Google Scholar
- [46]46. Tsai, W.W. ∙ Niessen, S. ∙ Goebel, N. ... PRMT5 modulates the metabolic response to fasting signals Proc. Natl. Acad. Sci. U.S.A. 2013; 110:8870-8875 Crossref Scopus (61) PubMed Google Scholar
- [48]48. Shiota, M. ∙ Izumi, H. ∙ Tanimoto, A. ... Programmed cell death protein 4 down-regulates Y-box binding protein-1 expression via a direct interaction with Twist1 to suppress cancer cell growth Cancer Res. 2009; 69:3148-3156 Crossref Scopus (119) PubMed Google Scholar
- [50]50. Leprivier, G. ∙ Remke, M. ∙ Rotblat, B. ... The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation Cell. 2013; 153:1064-1079 Full Text Full Text (PDF) Scopus (323) PubMed Google Scholar
Cited by
Sorted by citations
Tarighat, S. S., Santhanam, R., Frankhouser, D., Radomska, H. S., Lai, H., Anghelina, M., Wang, H., Huang, X., Alinari, L., Walker, A., et al. (2016) · Leukemia · doi:10.1038/leu.2015.308 · Cited by 169 · see citing works
Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions
Matsuhashi, S., Manirujjaman, M., Hamajima, H., & Ozaki, I. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092304 · Cited by 143 · see citing works
The role of Pdcd4 in tumour suppression and protein translation
Wang, Q., & Yang, H. (2018) · Biology of the Cell · doi:10.1111/boc.201800014 · Cited by 113 · see citing works
- Authors
- Fay, M. M., Clegg, J. M., Uchida, K. A., Powers, M. A., & Ullman, K. S.
- Affiliations
- Huntsman Cancer Institute (US)
- University of Utah (US)
- Corresponding author
- Ullman, Katharine S.
- ORCID
- Ullman, Katharine S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 289
- Issue
- 25
- Pages
- 17541-17552
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4067190
- OpenAlex
- W2093821263
- Cited by
- 30
- References
- 12
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 2
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (T32 CA093247, R21 CA173064, P30 CA042014)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- PDCD4, arginine methylation, PRMT5, nutrient deprivation, tumor cell viability, protein stability, phosphorylation, tumor suppressor, tumor growth
- MeSH terms
- Arginine, Cell Survival, Humans, Methylation, Neoplasm Proteins, Neoplasms, Phosphorylation, Protein-Arginine N-Methyltransferases, Up-Regulation, Gene Expression Regulation, Neoplastic, RNA-Binding Proteins, Cell Line, Tumor, Apoptosis Regulatory 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
