{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:09:25Z","timestamp":1766362165760,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:00:00Z","timestamp":1690329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"John Paul II University of Applied Sciences in Biala Podlaska\u2014project","award":["PB\/5\/2022"],"award-info":[{"award-number":["PB\/5\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The MCC family of genes plays a role in colorectal cancer development through various immunological pathways, including the Th17\/Treg axis. We have previously shown that MCC1 but not MCC2 plays a role in Treg differentiation. Our understanding of the genetic divergence patterns and evolutionary history of the MCC family in relation to its function, in general, and the Th17\/Treg axis, in particular, remains incomplete. In this investigation, we explored 12 species\u2019 genomes to study the phylogenetic origin, structure, and functional specificity of this family. In vertebrates, both MCC1 and MCC2 homologs have been discovered, while invertebrates have a single MCC homolog. We found MCC homologs as early as Cnidarians and Trichoplax, suggesting that the MCC family first appeared 741 million years ago (Ma), whereas MCC divergence into the MCC1 and MCC2 families occurred at 540 Ma. In general, we did not detect significant positive selection regulating MCC evolution. Our investigation, based on MCC1 structural similarity, suggests that they may play a role in the evolutionary changes in Tregs\u2019 emergence towards complexity, including the ability to utilize calcium for differentiation through the use of the EFH calcium-binding domain. We also found that the motif NPSTGE was highly conserved in MCC1, but not in MCC2. The NPSTGE motif binds KEAP1 with high affinity, suggesting an Nrf2-mediated function for MCC1. In the case of MCC2, we found that the \u201cmodifier of rudimentary\u201d motif is highly conserved. This motif contributes to the regulation of alternative splicing. Overall, our study sheds light on how the evolution of the MCC family is connected to its function in regulating the Th17\/Treg axis.<\/jats:p>","DOI":"10.3390\/ijms241511940","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T01:27:46Z","timestamp":1690421266000},"page":"11940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17\/Treg Differentiation"],"prefix":"10.3390","volume":"24","author":[{"given":"Norwin","family":"Kubick","sequence":"first","affiliation":[{"name":"Department of Biology, Institute of Plant Science and Microbiology, Univeristy of Hamburg, Ohnhorststr. 18, 22609 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justyna","family":"Paszkiewicz","sequence":"additional","affiliation":[{"name":"Department of Health, John Paul II University of Applied Sciences in Biala Podlaska, Sidorska 95\/97, 21-500 Bia\u0142a Podlaska, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irmina","family":"Bie\u0144kowska","sequence":"additional","affiliation":[{"name":"Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Post\u0119pu 36A, 05-552 Jastrz\u0119biec, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha\u0142","family":"\u0141awi\u0144ski","sequence":"additional","affiliation":[{"name":"Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Post\u0119pu 36A, 05-552 Jastrz\u0119biec, Poland"},{"name":"Department of General Surgery, Gastroenterology and Oncology, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaros\u0142aw Olav","family":"Horba\u0144czuk","sequence":"additional","affiliation":[{"name":"Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Post\u0119pu 36A, 05-552 Jastrz\u0119biec, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariusz","family":"Sacharczuk","sequence":"additional","affiliation":[{"name":"Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Post\u0119pu 36A, 05-552 Jastrz\u0119biec, Poland"},{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, l Banacha 1, 02-697 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel Edwar","family":"Mickael","sequence":"additional","affiliation":[{"name":"Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Post\u0119pu 36A, 05-552 Jastrz\u0119biec, Poland"},{"name":"PM Research Center, V\u00e4pnaregatan 22, 58649 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.4049\/jimmunol.2100175","article-title":"ROR\u03b3t Promotes Foxp3 Expression by Antagonizing the Effector Program in Colonic Regulatory T Cells","volume":"207","author":"Bhaumik","year":"2021","journal-title":"J. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1016\/j.ajpath.2020.07.010","article-title":"Retinoid-Related Orphan Receptor ROR\u03b3t in CD4+ T Cell Mediated Intestinal Homeostasis and Inflammation","volume":"190","author":"Mickael","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.4049\/jimmunol.2100869","article-title":"ROR\u03b3t-Expressing Pathogenic CD4+ T Cells Cause Brain Inflammation during Chronic Colitis","volume":"208","author":"Mickael","year":"2022","journal-title":"J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1136\/gutjnl-2015-310016","article-title":"Dual Role of Tumour-Infiltrating T Helper 17 Cells in Human Colorectal Cancer","volume":"66","author":"Amicarella","year":"2017","journal-title":"Gut"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"628","DOI":"10.3390\/cimb45010042","article-title":"Investigation of the Molecular Evolution of Treg Suppression Mechanisms Indicates a Convergent Origin","volume":"45","author":"Bhaumik","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"doi-asserted-by":"crossref","unstructured":"Olgu\u00edn, J.E., Medina-Andrade, I., Rodr\u00edguez, T., Rodr\u00edguez-Sosa, M., and Terrazas, L.I. (2020). Relevance of Regulatory T Cells during Colorectal Cancer Development. Cancers, 12.","key":"ref_6","DOI":"10.3390\/cancers12071888"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1016\/j.bbadis.2016.05.009","article-title":"Frequent Inactivation of MCC\/CTNNBIP1 and Overexpression of Phospho-Beta-Catenin Y654 Are Associated with Breast Carcinoma: Clinical and Prognostic Significance","volume":"1862","author":"Mukherjee","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.clbc.2020.04.004","article-title":"Wnt\/\u03b2-Catenin Signaling Pathway as Chemotherapeutic Target in Breast Cancer: An Update on Pros and Cons","volume":"20","author":"Mukherjee","year":"2020","journal-title":"Clin. Breast Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13045-014-0056-6","article-title":"Mutated in Colorectal Cancer (MCC) Is a Novel Oncogene in B Lymphocytes","volume":"7","author":"Edwards","year":"2014","journal-title":"J. Hematol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1002\/dvdy.22712","article-title":"Mutated in Colorectal Cancer (Mcc), a Candidate Tumor Suppressor, Is Dynamically Expressed during Mouse Embryogenesis","volume":"240","author":"Young","year":"2011","journal-title":"Dev. Dyn."},{"key":"ref_11","first-page":"79","article-title":"Transcriptome Analysis of the Th17\/Treg Axis Reveals Multiple Pathways That Ensure Distinct Differentiation Patterns","volume":"41","author":"Mickael","year":"2023","journal-title":"Anim. Sci. Pap. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF02456615","article-title":"Modifier of RudimentaryP1, Mod(r)P1, a Trans-Acting Regulatory Mutation of Rudimentary","volume":"248","author":"Begley","year":"1995","journal-title":"Mol. Gen. Genet. MGG"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4337","DOI":"10.1091\/mbc.e04-03-0250","article-title":"The Growth-Regulatory Protein HCRP1\/h Vps37A Is a Subunit of Mammalian ESCRT-I and Mediates Receptor down-Regulation","volume":"15","author":"Bache","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1016\/j.str.2011.09.020","article-title":"Crystallographic Analysis of Polypyrimidine Tract-Binding Protein-Raver1 Interactions Involved in Regulation of Alternative Splicing","volume":"19","author":"Joshi","year":"2011","journal-title":"Structure"},{"unstructured":"Peng, X., Nelson, E.S., Maiers, J.L., and DeMali, K.A. (2011). International Review of Cell and Molecular Biology, Elsevier.","key":"ref_15"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5115","DOI":"10.1073\/pnas.1220271110","article-title":"E3 Ligase WWP2 Negatively Regulates TLR3-Mediated Innate Immune Response by Targeting TRIF for Ubiquitination and Degradation","volume":"110","author":"Yang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"R608","DOI":"10.1016\/S0960-9822(00)00633-3","article-title":"Notch Signaling: Fringe Really Is a Glycosyltransferase","volume":"10","author":"Blair","year":"2000","journal-title":"Curr. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s000180300019","article-title":"O-Fucose Modifications of Epidermal Growth Factor-like Repeats and Thrombospondin Type 1 Repeats: Unusual Modifications in Unusual Places","volume":"60","author":"Shao","year":"2003","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.canlet.2008.09.030","article-title":"Emerging Role of Notch in Stem Cells and Cancer","volume":"279","author":"Wang","year":"2009","journal-title":"Cancer Lett."},{"doi-asserted-by":"crossref","unstructured":"M\u00e1rton, M., Tihanyi, N., Gyulav\u00e1ri, P., B\u00e1nhegyi, G., and Kapuy, O. (2018). NRF2-Regulated Cell Cycle Arrest at Early Stage of Oxidative Stress Response Mechanism. PLoS ONE, 13.","key":"ref_20","DOI":"10.1371\/journal.pone.0207949"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.freeradbiomed.2020.03.023","article-title":"Beyond Repression of Nrf2: An Update on Keap1","volume":"157","author":"Kopacz","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"903564","DOI":"10.3389\/fimmu.2022.903564","article-title":"Colorectal Cancer-Infiltrating Regulatory T Cells: Functional Heterogeneity, Metabolic Adaptation, and Therapeutic Targeting","volume":"13","author":"Kranenburg","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0959-440X(00)00142-1","article-title":"EF-Hand Calcium-Binding Proteins","volume":"10","year":"2000","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1021\/ar100110d","article-title":"Relating Form and Function of EF-Hand Calcium Binding Proteins","volume":"44","author":"Chazin","year":"2011","journal-title":"Acc. Chem. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/(SICI)1097-0134(19991115)37:3<499::AID-PROT17>3.0.CO;2-Y","article-title":"Diversity of Conformational States and Changes within the EF-Hand Protein Superfamily","volume":"37","author":"Yap","year":"1999","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.molmed.2007.01.003","article-title":"Natural Regulatory T Cells: Mechanisms of Suppression","volume":"13","author":"Miyara","year":"2007","journal-title":"Trends Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1007\/s00775-006-0163-0","article-title":"EF-Hand Protein Dynamics and Evolution of Calcium Signal Transduction: An NMR View","volume":"11","author":"Capozzi","year":"2006","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_28","first-page":"85","article-title":"An Optimised Phylogenetic Method Sheds More Light on the Main Branching Events of Rhodopsin-like Superfamily","volume":"20","author":"Mickael","year":"2016","journal-title":"Comp. Biochem. Physiol. Part D Genom. Proteom."},{"doi-asserted-by":"crossref","unstructured":"Kubick, N., Klimovich, P., Bie\u0144kowska, I., Poznanski, P., \u0141azarczyk, M., Sacharczuk, M., and Mickael, M.-E. (2021). Investigation of Evolutionary History and Origin of the Tre1 Family Suggests a Role in Regulating Hemocytes Cells Infiltration of the Blood\u2013Brain Barrier. Insects, 12.","key":"ref_29","DOI":"10.1101\/2021.04.29.441935"},{"doi-asserted-by":"crossref","unstructured":"Mickael, M.E., Bie\u0144kowska, I., and Sacharczuk, M. (2022). An Update on the Evolutionary History of Bregs. Genes, 13.","key":"ref_30","DOI":"10.3390\/genes13050890"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/pro.4172","article-title":"KEGG Mapping Tools for Uncovering Hidden Features in Biological Data","volume":"31","author":"Kanehisa","year":"2022","journal-title":"Protein Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/molbev\/msm088","article-title":"PAML 4: Phylogenetic Analysis by Maximum Likelihood","volume":"24","author":"Yang","year":"2007","journal-title":"Mol. Biol. Evol."},{"doi-asserted-by":"crossref","unstructured":"Mickael, M.-E., Kubick, N., Gurba, A., Klimovich, P., Bie\u0144kowska, I., Kocki, T., and Sacharczuk, M. (2022). Fezf2 and Aire1 Evolutionary Trade-off in Negative Selection of T Cells in the Thymus. bioRxiv.","key":"ref_33","DOI":"10.1101\/2022.02.01.478624"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/11940\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:19:04Z","timestamp":1760127544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/11940"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,26]]},"references-count":33,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241511940"],"URL":"https:\/\/doi.org\/10.3390\/ijms241511940","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,7,26]]}}}