{"doi":"10.1073/pnas.95.18.10407","title":"Ribonuclease A variants with potent cytotoxic activity","abstract":"<jats:p>Select members of the bovine pancreatic ribonuclease A (RNase A) superfamily are potent cytotoxins. These cytotoxic ribonucleases enter the cytosol, where they degrade cellular RNA and cause cell death. Ribonuclease inhibitor (RI), a cytosolic protein, binds to members of the RNase A superfamily with inhibition constants that span 10 orders of magnitude. Here, we show that the affinity of a ribonuclease for RI plays an integral role in defining the potency of a cytotoxic ribonuclease. RNase A is not cytotoxic and binds RI with high affinity. Onconase, a cytotoxic RNase A homolog, binds RI with low affinity. To disrupt the RI-RNase A interaction, three RNase A residues (Asp-38, Gly-88, and Ala-109) that form multiple contacts with RI were replaced with arginine. Replacing Asp-38 and Ala-109 with an arginine residue has no effect on the RI–RNase interaction. In addition, these variants are not cytotoxic. In contrast, replacing Gly-88 with an arginine residue yields a ribonuclease (G88R RNase A) that retains catalytic activity in the presence of RI and is cytotoxic to a transformed cell line. Replacing Gly-88 with aspartate also yields a ribonuclease (G88D RNase A) with a decreased affinity for RI and cytotoxic activity. The cytotoxic potency of onconase, G88R RNase A, and G88D RNase A correlate with RI evasion. We conclude that ribonucleases that retain catalytic activity in the presence of RI are cytotoxins. This finding portends the development of a class of chemotherapeutic agents based on pancreatic ribonucleases.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":1998,"id":45248,"datarank":9.855297067016227,"base_score":5.393627546352361,"endowment":5.393627546352361,"self_citation_contribution":0.8090441319528543,"citation_network_contribution":9.046252935063373,"self_endowment_contribution":0.8090441319528543,"citer_contribution":9.046252935063373,"corpus_percentile":null,"corpus_rank":null,"citation_count":219,"citer_count":165,"citers_with_citation_signal":153,"citers_with_endowment":153,"datacite_reuse_total":2,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":211691,"name":"L. Wayne Schultz","orcid":null,"position":1,"is_corresponding":false},{"id":211692,"name":"Byung-Moon Kim","orcid":null,"position":2,"is_corresponding":false},{"id":119492,"name":"Ronald T. Raines","orcid":null,"position":3,"is_corresponding":false},{"id":211690,"name":"Peter A. Leland","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.393627546352361,"endowment":5.393627546352361,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"9724716","pmcid":"PMC27907","openalex_id":"https://openalex.org/W2089717292","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"CA69750","title":null},{"funder_name":"NCI NIH HHS","grant_id":"F32 CA069750","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM07215","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM007215","title":null}],"total_grants":4,"fwci":6.7014,"citation_percentile":0.97027838,"influential_citations":9,"citation_trend":[{"year":2012,"count":6},{"year":2013,"count":5},{"year":2014,"count":6},{"year":2015,"count":6},{"year":2016,"count":7},{"year":2017,"count":7},{"year":2018,"count":3},{"year":2019,"count":3},{"year":2020,"count":4},{"year":2021,"count":6},{"year":2022,"count":3},{"year":2023,"count":5},{"year":2024,"count":1},{"year":2025,"count":6}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/27907","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc27907?pdf=render","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/27907","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.95.18.10407","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.95.18.10407","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/9724716","host_type":"repository"}],"fields_of_study":["Bacterial Genetics and Biotechnology","RNA Interference and Gene Delivery","CRISPR and Genetic Engineering","Biology","Medicine","Animals","Cattle","Cell Survival","Enzyme Inhibitors","Enzyme Stability","Kinetics","Recombinant Proteins","Ribonuclease, Pancreatic","Tumor Cells, Cultured"],"mesh_terms":["Animals","Cattle","Cell Survival","Enzyme Inhibitors","Enzyme Stability","Kinetics","Recombinant Proteins","Ribonuclease, Pancreatic","Tumor Cells, Cultured"],"keywords":["Ribonuclease","RNase P","Pancreatic ribonuclease","Cytotoxic T cell","Bovine pancreatic ribonuclease","S-tag","RNase MRP","Biochemistry","Molecular biology","RNase H","Biology","Cytotoxicity","Chemistry","RNA","In vitro"],"sdg_mappings":[],"linked_datasets":[{"doi":"10.6084/m9.figshare.16880092.v1","title":"Additional file 1 of Ribonuclease zymogen induces cytotoxicity upon HIV-1 infection","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.16880092","title":"Additional file 1 of Ribonuclease zymogen induces cytotoxicity upon HIV-1 infection","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-02T09:44:54.754863Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}