Cargando…

Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation

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 hist...

Descripción completa

Detalles Bibliográficos
Autores principales: Kubick, Norwin, Paszkiewicz, Justyna, Bieńkowska, Irmina, Ławiński, Michał, Horbańczuk, Jarosław Olav, Sacharczuk, Mariusz, Mickael, Michel Edwar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418881/
https://www.ncbi.nlm.nih.gov/pubmed/37569317
http://dx.doi.org/10.3390/ijms241511940
_version_ 1785088375074586624
author Kubick, Norwin
Paszkiewicz, Justyna
Bieńkowska, Irmina
Ławiński, Michał
Horbańczuk, Jarosław Olav
Sacharczuk, Mariusz
Mickael, Michel Edwar
author_facet Kubick, Norwin
Paszkiewicz, Justyna
Bieńkowska, Irmina
Ławiński, Michał
Horbańczuk, Jarosław Olav
Sacharczuk, Mariusz
Mickael, Michel Edwar
author_sort Kubick, Norwin
collection PubMed
description 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’ 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’ 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 “modifier of rudimentary” 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.
format Online
Article
Text
id pubmed-10418881
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-104188812023-08-12 Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation Kubick, Norwin Paszkiewicz, Justyna Bieńkowska, Irmina Ławiński, Michał Horbańczuk, Jarosław Olav Sacharczuk, Mariusz Mickael, Michel Edwar Int J Mol Sci Article 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’ 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’ 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 “modifier of rudimentary” 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. MDPI 2023-07-26 /pmc/articles/PMC10418881/ /pubmed/37569317 http://dx.doi.org/10.3390/ijms241511940 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kubick, Norwin
Paszkiewicz, Justyna
Bieńkowska, Irmina
Ławiński, Michał
Horbańczuk, Jarosław Olav
Sacharczuk, Mariusz
Mickael, Michel Edwar
Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation
title Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation
title_full Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation
title_fullStr Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation
title_full_unstemmed Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation
title_short Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation
title_sort investigation of mutated in colorectal cancer (mcc) gene family evolution history indicates a putative role in th17/treg differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418881/
https://www.ncbi.nlm.nih.gov/pubmed/37569317
http://dx.doi.org/10.3390/ijms241511940
work_keys_str_mv AT kubicknorwin investigationofmutatedincolorectalcancermccgenefamilyevolutionhistoryindicatesaputativeroleinth17tregdifferentiation
AT paszkiewiczjustyna investigationofmutatedincolorectalcancermccgenefamilyevolutionhistoryindicatesaputativeroleinth17tregdifferentiation
AT bienkowskairmina investigationofmutatedincolorectalcancermccgenefamilyevolutionhistoryindicatesaputativeroleinth17tregdifferentiation
AT ławinskimichał investigationofmutatedincolorectalcancermccgenefamilyevolutionhistoryindicatesaputativeroleinth17tregdifferentiation
AT horbanczukjarosławolav investigationofmutatedincolorectalcancermccgenefamilyevolutionhistoryindicatesaputativeroleinth17tregdifferentiation
AT sacharczukmariusz investigationofmutatedincolorectalcancermccgenefamilyevolutionhistoryindicatesaputativeroleinth17tregdifferentiation
AT mickaelmicheledwar investigationofmutatedincolorectalcancermccgenefamilyevolutionhistoryindicatesaputativeroleinth17tregdifferentiation