{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T21:22:19Z","timestamp":1776892939887,"version":"3.51.2"},"reference-count":47,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CIBERER (Spain)","award":["ERPR07G772"],"award-info":[{"award-number":["ERPR07G772"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The PTEN tumor suppressor is frequently targeted in tumors and patients with PTEN hamartoma tumor syndrome (PHTS) through nonsense mutations generating premature termination codons (PTC) that may cause the translation of truncated non-functional PTEN proteins. We have previously described a global analysis of the readthrough reconstitution of the protein translation and function of the human canonical PTEN isoform by aminoglycosides. Here, we report the efficient functional readthrough reconstitution of the PTEN translational isoform PTEN-L, which displays a minimal number of PTC in its specific N-terminal extension in association with disease. We illustrate the importance of the specific PTC and its nucleotide proximal sequence for optimal readthrough and show that the more frequent human PTEN PTC variants and their mouse PTEN PTC equivalents display similar patterns of readthrough efficiency. The heterogeneous readthrough response of the different PTEN PTC variants was independent of the length of the PTEN protein being reconstituted, and we found a correlation between the amount of PTEN protein being synthesized and the PTEN readthrough efficiency. Furthermore, combination of aminoglycosides and protein synthesis inducers increased the readthrough response of specific PTEN PTC. Our results provide insights with which to improve the functional reconstitution of human-disease-related PTC pathogenic variants from PTEN isoforms by increasing protein synthesis coupled to translational readthrough.<\/jats:p>","DOI":"10.3390\/cancers16162836","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T10:54:54Z","timestamp":1723546494000},"page":"2836","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Potentiation by Protein Synthesis Inducers of Translational Readthrough of Pathogenic Premature Termination Codons in PTEN Isoforms"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2315-1218","authenticated-orcid":false,"given":"Leire","family":"Torices","sequence":"first","affiliation":[{"name":"Biobizkaia Health Research Institute, 48903 Barakaldo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1875-6645","authenticated-orcid":false,"given":"Caroline E.","family":"Nunes-Xavier","sequence":"additional","affiliation":[{"name":"Biobizkaia Health Research Institute, 48903 Barakaldo, Spain"},{"name":"Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, CIBERER, ISCIII, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Pulido","sequence":"additional","affiliation":[{"name":"Biobizkaia Health Research Institute, 48903 Barakaldo, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, CIBERER, ISCIII, 28029 Madrid, Spain"},{"name":"Ikerbasque, The Basque Foundation for Science, 48009 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41580-018-0015-0","article-title":"The functions and regulation of the PTEN tumour suppressor: New modes and prospects","volume":"19","author":"Lee","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0962-8924(99)01519-6","article-title":"PTEN: A tumour suppressor that functions as a phospholipid phosphatase","volume":"9","author":"Maehama","year":"1999","journal-title":"Trends Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ymeth.2015.02.009","article-title":"PTEN: A yin-yang master regulator protein in health and disease","volume":"77\u201378","author":"Pulido","year":"2015","journal-title":"Methods"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103197","DOI":"10.1016\/j.dnarep.2021.103197","article-title":"Non-canonical function of nuclear PTEN and its implication on tumorigenesis","volume":"107","author":"Misra","year":"2021","journal-title":"DNA Repair"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Papa, A., and Pandolfi, P.P. (2016). Phosphatase-independent functions of the tumor suppressor PTEN. Protein Tyrosine Phosphatases in Cancer, Springer.","DOI":"10.1007\/978-1-4939-3649-6_9"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.semcancer.2019.02.001","article-title":"Mechanisms of PTEN loss in cancer: It\u2019s all about diversity","volume":"59","author":"Tawil","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"a036293","DOI":"10.1101\/cshperspect.a036293","article-title":"Precise Immunodetection of PTEN Protein in Human Neoplasia","volume":"9","author":"Pulido","year":"2019","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.conb.2012.05.004","article-title":"PTEN signaling in autism spectrum disorders","volume":"22","author":"Zhou","year":"2012","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1126\/science.1234907","article-title":"A secreted PTEN phosphatase that enters cells to alter signaling and survival","volume":"341","author":"Hopkins","year":"2013","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.cmet.2014.03.023","article-title":"PTENalpha, a PTEN Isoform Translated through Alternative Initiation, Regulates Mitochondrial Function and Energy Metabolism","volume":"19","author":"Liang","year":"2014","journal-title":"Cell Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"pe15","DOI":"10.1126\/scisignal.2005560","article-title":"A Unified Nomenclature and Amino Acid Numbering for Human PTEN","volume":"7","author":"Pulido","year":"2014","journal-title":"Sci. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tzani, I., Ivanov, I.P., Andreev, D.E., Dmitriev, R.I., Dean, K.A., Baranov, P.V., Atkins, J.F., and Loughran, G. (2016). Systematic analysis of the PTEN 5\u2032 leader identifies a major AUU initiated proteoform. Open Biol., 6.","DOI":"10.1098\/rsob.150203"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a036087","DOI":"10.1101\/cshperspect.a036087","article-title":"PTEN in Hereditary and Sporadic Cancer","volume":"10","author":"Ngeow","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1146\/annurev-med-052218-125823","article-title":"The Clinical Spectrum of PTEN Mutations","volume":"71","author":"Yehia","year":"2020","journal-title":"Annu. Rev. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-0716-3569-8_1","article-title":"Induction of Translational Readthrough on Protein Tyrosine Phosphatases Targeted by Premature Termination Codon Mutations in Human Disease","volume":"2743","author":"Torices","year":"2024","journal-title":"Methods Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.tig.2020.11.002","article-title":"To NMD or Not To NMD: Nonsense-Mediated mRNA Decay in Cancer and Other Genetic Diseases","volume":"37","author":"Supek","year":"2021","journal-title":"Trends Genet. TIG"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s10020-018-0024-7","article-title":"Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons","volume":"24","author":"Dabrowski","year":"2018","journal-title":"Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1146\/annurev-genom-091212-153527","article-title":"Therapeutics based on stop codon readthrough","volume":"15","author":"Keeling","year":"2014","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4677","DOI":"10.1007\/s00018-021-03809-7","article-title":"Nonsense suppression therapies in human genetic diseases","volume":"78","author":"Romao","year":"2021","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/978-3-031-27681-1_23","article-title":"Factors Affecting Readthrough of Natural Versus Premature Termination Codons","volume":"1415","author":"Beryozkin","year":"2023","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1080\/15476286.2015.1068497","article-title":"Translational readthrough potential of natural termination codons in eucaryotes--The impact of RNA sequence","volume":"12","author":"Dabrowski","year":"2015","journal-title":"RNA Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, S., Li, J., Shi, W., Nie, Z., Zhang, S., Ma, F., Hu, J., Chen, J., Li, P., and Xie, X. (2023). Pharmaceuticals Promoting Premature Termination Codon Readthrough: Progress in Development. Biomolecules, 13.","DOI":"10.3390\/biom13060988"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.molmed.2023.01.004","article-title":"Readthrough compounds for nonsense mutations: Bridging the translational gap","volume":"29","author":"Spelier","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hosseini-Farahabadi, S., Baradaran-Heravi, A., Zimmerman, C., Choi, K., Flibotte, S., and Roberge, M. (2021). Small molecule Y-320 stimulates ribosome biogenesis, protein synthesis, and aminoglycoside-induced premature termination codon readthrough. PLoS Biol., 19.","DOI":"10.1371\/journal.pbio.3001221"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wittenstein, A., Caspi, M., Rippin, I., Elroy-Stein, O., Eldar-Finkelman, H., Thoms, S., and Rosin-Arbesfeld, R. (2023). Nonsense mutation suppression is enhanced by targeting different stages of the protein synthesis process. PLoS Biol., 21.","DOI":"10.1371\/journal.pbio.3002355"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/humu.24186","article-title":"A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons","volume":"42","author":"Luna","year":"2021","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D835","DOI":"10.1093\/nar\/gkz972","article-title":"ClinVar: Improvements to accessing data","volume":"48","author":"Landrum","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","article-title":"The Human Gene Mutation Database (HGMD((R))): Optimizing its use in a clinical diagnostic or research setting","volume":"139","author":"Stenson","year":"2020","journal-title":"Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4002","DOI":"10.1091\/mbc.e06-05-0380","article-title":"Nuclear localization of PTEN by a Ran-dependent mechanism enhances apoptosis: Involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs","volume":"17","author":"Gil","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1038\/s41431-018-0155-x","article-title":"A pathogenic role for germline PTEN variants which accumulate into the nucleus","volume":"26","author":"Mingo","year":"2018","journal-title":"Eur. J. Hum. Genet. EJHG"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1111\/j.1523-1747.2003.12638.x","article-title":"A novel loss-of-function mutation (N48K) in the PTEN gene in a Spanish patient with Cowden disease","volume":"121","author":"Vega","year":"2003","journal-title":"J. Investig. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Torices, L., Nunes-Xavier, C.E., Lopez, J.I., and Pulido, R. (2023). Novel anti-PTEN C2 domain monoclonal antibodies to analyze the expression and function of PTEN isoform variants. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0289369"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100710","DOI":"10.1016\/j.ymgmr.2021.100710","article-title":"MMADHC premature termination codons in the pathogenesis of cobalamin D disorder: Potential of translational readthrough reconstitution","volume":"26","author":"Torices","year":"2021","journal-title":"Mol. Genet Metab. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1074\/jbc.M009134200","article-title":"The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation","volume":"276","author":"Torres","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mingo, J., Erramuzpe, A., Luna, S., Aurtenetxe, O., Amo, L., Diez, I., Schepens, J.T., Hendriks, W.J., Cortes, J.M., and Pulido, R. (2016). One-Tube-Only Standardized Site-Directed Mutagenesis: An Alternative Approach to Generate Amino Acid Substitution Collections. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160972"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41698-019-0083-4","article-title":"Precise definition of PTEN C-terminal epitopes and its implications in clinical oncology","volume":"3","author":"Mingo","year":"2019","journal-title":"NPJ Precis. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/BF00986964","article-title":"Signal transduction mechanisms in the regulation of protein synthesis","volume":"19","author":"Morley","year":"1994","journal-title":"Mol. Biol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1016\/S0021-9258(18)53649-8","article-title":"Regulation of eukaryotic protein synthesis by initiation factors","volume":"268","author":"Rhoads","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1007\/s12640-022-00475-w","article-title":"The Role of PTEN-L in Modulating PINK1-Parkin-Mediated Mitophagy","volume":"40","author":"Eldeeb","year":"2022","journal-title":"Neurotox. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5379","DOI":"10.1158\/1078-0432.CCR-13-2661","article-title":"Molecular pathways: Intercellular PTEN and the potential of PTEN restoration therapy","volume":"20","author":"Hopkins","year":"2014","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, L., Lu, G., and Shen, H.M. (2020). The Long and the Short of PTEN in the Regulation of Mitophagy. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00299"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.molcel.2021.01.033","article-title":"Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis","volume":"81","author":"Mukherjee","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/ana.22024","article-title":"Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy","volume":"67","author":"Malik","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/bjd.18718","article-title":"Treatment of hereditary hypotrichosis simplex of the scalp with topical gentamicin","volume":"183","author":"Peled","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Sermet-Gaudelus, I., Renouil, M., Fajac, A., Bidou, L., Parbaille, B., Pierrot, S., Davy, N., Bismuth, E., Reinert, P., and Lenoir, G. (2007). In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: A pilot study. BMC Med., 5.","DOI":"10.1186\/1741-7015-5-5"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1080\/14740338.2020.1712357","article-title":"Protective effects of pharmacological agents against aminoglycoside-induced nephrotoxicity: A systematic review","volume":"19","author":"Yaghoubi","year":"2020","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1080\/15476286.2023.2222250","article-title":"Novel compounds that synergize with aminoglycoside G418 or eRF3 degraders for translational readthrough of nonsense mutant TP53 and PTEN","volume":"20","author":"Heldin","year":"2023","journal-title":"RNA Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/16\/2836\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:35:59Z","timestamp":1760110559000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/16\/2836"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,13]]},"references-count":47,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["cancers16162836"],"URL":"https:\/\/doi.org\/10.3390\/cancers16162836","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,13]]}}}