{"id":66827,"date":"2024-03-06T11:46:46","date_gmt":"2024-03-06T10:46:46","guid":{"rendered":"https:\/\/www.embl.org\/news\/?p=66827"},"modified":"2024-03-22T11:41:35","modified_gmt":"2024-03-22T10:41:35","slug":"studying-the-relationship-between-cancer-promoting-proteins","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/studying-the-relationship-between-cancer-promoting-proteins\/","title":{"rendered":"Studying the relationship between cancer-promoting proteins"},"content":{"rendered":"\n<p><em>By Simonne Griffith-Jones, Predoctoral Fellow, EMBL Grenoble<\/em><\/p>\n\n\n\n<article class=\"vf-card vf-card--brand vf-card--bordered vf-u-margin__bottom--800\" default>\n  <div class=\"vf-card__content | vf-stack vf-stack--400\">\n      <h3 class=\"vf-card__heading\">\n      Summary    <\/h3>\n                <p class=\"vf-card__text\"><ul>\r\n<li>The protein MAGEA4 contributes to cancer survival by preventing the degradation of a cancer-promoting protein called RAD18, which is implicated in resistance to certain kinds of chemotherapy and radiotherapy.\r\n<\/li><li>Researchers from the Bhogaraju group at EMBL Grenoble have studied the structure of the MAGEA4-RAD18 complex and identified a hotspot that is necessary for this interaction. \r\n<\/li><li>The structural insights gained from this study could help in the design of anti-cancer therapeutics targeted towards preventing the binding of RAD18 to its partner proteins. <\/li><\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>Researchers from the Bhogaraju Group at EMBL Grenoble have gained new insights into how a cancer-relevant family of proteins bind their targets. The results of the study, <a href=\"https:\/\/www.embopress.org\/doi\/full\/10.1038\/s44318-024-00058-9\" target=\"_blank\" rel=\"noreferrer noopener\">published in <em>The EMBO Journal<\/em><\/a>, could potentially help in the development of drugs against certain chemotherapy- and radiotherapy-resistant cancers.\u00a0\u00a0<\/p>\n\n\n\n<p>The Melanoma Antigen Gene (MAGE) family consists of more than 40 proteins in humans, most of which are only present in the testes under healthy conditions. However, in many cancers, these proteins are found in high levels in tissues where they are not usually expressed and are believed to play a role in promoting cancer progression.&nbsp;<\/p>\n\n\n\n<p>One such MAGE protein \u2013 MAGEA4 \u2013 is known to interact with RAD18, a protein known to be abundant in some cancer cells. The latter is part of the molecular machinery that helps the cell repair damage to its DNA. High levels of RAD18 are responsible for the resistance of several cancers to genotoxic (DNA-damaging) chemotherapy or radiotherapy.&nbsp;&nbsp;<\/p>\n\n\n\n<p>RAD18 functions by attaching little molecular tags \u2013 called ubiquitin \u2013 to different proteins. This tag, like a postal stamp, tells the cell what the fate of that protein would be. RAD18 can also attach this tag to itself \u2013 a process called autoubiquitination. This targets it for degradation, i.e. tells the cell to get rid of excess levels of this protein.&nbsp;<\/p>\n\n\n\n<p>The Bhogaraju Group at EMBL Grenoble uses structural and cell biology-based approaches to study such ubiquitin-based pathways in normal physiology and disease. The team, in collaboration with the <a href=\"https:\/\/www.embl.org\/groups\/hennig\/\">Hennig Group<\/a> at EMBL Heidelberg, decided to look more deeply into the interaction between the proteins MAGEA4 and RAD18, using <a href=\"https:\/\/www.embl.org\/about\/info\/annual-report\/ar2021\/alphafold-a-game-changer-for-structural-biology\">AlphaFold<\/a>, an artificial-intelligence based tool that allows scientists to predict the structure of proteins.&nbsp;<\/p>\n\n\n\n<p>The team, which included Bhogaraju Group PhD student Simonne Griffith-Jones and postdoc Urbi Mukhopadhyay, found that MAGEA4 has a groove that can bind a section of the RAD18 protein, which prevents the latter from attaching ubiquitin groups to itself and subsequently getting degraded.&nbsp;<\/p>\n\n\n\n<p>Interestingly, the researchers could use a short synthetic protein fragment, mimicking the part of RAD18 that binds the groove in MAGEA4, to block the interaction between the two proteins. This could potentially pave the way for the design of drugs that target this complex and prevent RAD18 build-up within cancer cells.&nbsp;<\/p>\n\n\n\n<p>The researchers also found a very similar groove in another MAGE family protein, which is used to regulate a different cancer-promoting protein. They believe this groove may be a general feature of the MAGE family, used to mediate binding to cancer-relevant proteins.<\/p>\n\n\n\n<p>\u200b\u200bIn addition to the groove, the scientists also observed that two parts within the RAD18 protein interact with each other, which helps it attach the ubiquitin tag to a protein which promotes cancer cell survival. They could block this function using genetic strategies, implying that future drugs designed to block this interaction could potentially re-sensitise cancer cells which have gained resistance to chemotherapies or radiotherapies.<\/p>\n\n\n\n<p>&nbsp;\u201cWe are excited with these data because our findings seem to be applicable to many MAGEs opening a gateway into targeting MAGEs which drive cancers,\u201d said Sagar Bhogaraju, Group Leader at EMBL Grenoble.\u201cWe are currently working on developing methods to screen compounds that bind the newly discovered hotspot of MAGEs.\u201d<\/p>\n\n\n\n<hr class=\"vf-divider\"\/>\n\n\n\n<h1 class=\"wp-block-heading\" id=\"french\"><strong>\u00c9tudier la relation entre les prot\u00e9ines favorisant le d\u00e9veloppement de cancers<\/strong><\/h1>\n\n\n\n<h2 class=\"wp-block-heading\">Une nouvelle \u00e9tude du groupe de recherche de Sagar Bhogaraju \u00e0 l&#8217;EMBL Grenoble r\u00e9v\u00e8le comment les prot\u00e9ines de la famille MAGE, qui contribuent au d\u00e9veloppement de cancers, se lient \u00e0 leurs cibles. Cette d\u00e9couverte faciliterait la mise au point de m\u00e9dicaments anticanc\u00e9reux ciblant ces prot\u00e9ines<\/h2>\n\n\n\n<article class=\"vf-card vf-card--brand vf-card--bordered vf-u-margin__bottom--800\" default>\n  <div class=\"vf-card__content | vf-stack vf-stack--400\">\n      <h3 class=\"vf-card__heading\">\n      R\u00e9sum\u00e9    <\/h3>\n                <p class=\"vf-card__text\"><ul>\r\n<li>La prot\u00e9ine MAGEA4 contribue \u00e0 la survie de cancers en emp\u00eachant la d\u00e9gradation d&#8217;une prot\u00e9ine promotrice du cancer appel\u00e9e RAD18, qui est impliqu\u00e9e dans la r\u00e9sistance \u00e0 certains types de chimioth\u00e9rapie et de radioth\u00e9rapie.\r\n<\/li><li>Des chercheurs du groupe Bhogaraju de l&#8217;EMBL Grenoble ont \u00e9tudi\u00e9 la structure du complexe MAGEA4-RAD18 et ont identifi\u00e9 un point critique n\u00e9cessaire \u00e0 cette interaction. \r\n<\/li><li>Les connaissances structurelles acquises gr\u00e2ce \u00e0 cette \u00e9tude pourraient contribuer \u00e0 la conception de traitements anticanc\u00e9reux visant \u00e0 emp\u00eacher la liaison de RAD18 \u00e0 ses prot\u00e9ines partenaires.\r\n<\/li><\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>Des chercheurs du groupe de Sagar Bhogaraju de l&#8217;EMBL Grenoble ont acquis de nouvelles connaissances sur la mani\u00e8re dont une famille de prot\u00e9ines impliqu\u00e9es dans le d\u00e9veloppement de cancers se lie \u00e0 leurs cibles. Les r\u00e9sultats de l&#8217;\u00e9tude, <a href=\"https:\/\/www.embopress.org\/doi\/full\/10.1038\/s44318-024-00058-9\" target=\"_blank\" rel=\"noreferrer noopener\">publi\u00e9s dans <em>The<\/em> <em>EMBO Journal<\/em><\/a>, pourraient potentiellement aider au d\u00e9veloppement de m\u00e9dicaments contre certains cancers r\u00e9sistants \u00e0 la chimioth\u00e9rapie et \u00e0 la radioth\u00e9rapie.\u00a0\u00a0<\/p>\n\n\n\n<p>La famille Melanoma Antigen Gene (MAGE) comprend plus de 40 prot\u00e9ines chez l&#8217;homme, dont la plupart ne se trouvent que dans les testicules sains. Cependant, dans de nombreux cancers, ces prot\u00e9ines sont pr\u00e9sentes en grande quantit\u00e9 dans des tissus o\u00f9 elles ne sont pas habituellement exprim\u00e9es. Celles-ci joueraient donc un r\u00f4le favorisant la progression de cancers.&nbsp;<\/p>\n\n\n\n<p>L&#8217;une de ces prot\u00e9ines MAGE (MAGEA4) est connue pour interagir avec RAD18, une prot\u00e9ine que l\u2019on trouve en grande quantit\u00e9 dans certaines cellules canc\u00e9reuses. Cette derni\u00e8re fait partie de la machinerie mol\u00e9culaire qui aide la cellule \u00e0 r\u00e9parer les dommages caus\u00e9s \u00e0 son ADN. Des niveaux \u00e9lev\u00e9s de RAD18 sont responsables de la r\u00e9sistance de plusieurs cancers \u00e0 la chimioth\u00e9rapie ou \u00e0 la radioth\u00e9rapie g\u00e9notoxique (qui endommage l&#8217;ADN).&nbsp;&nbsp;<\/p>\n\n\n\n<p>La prot\u00e9ine RAD18 fonctionne en attachant de petites \u00e9tiquettes mol\u00e9culaires &#8211; appel\u00e9es ubiquitine &#8211; \u00e0 diff\u00e9rentes prot\u00e9ines. Cette \u00e9tiquette, tel un timbre postal, indique \u00e0 la cellule le sort qui sera r\u00e9serv\u00e9 \u00e0 une prot\u00e9ine. RAD18 peut \u00e9galement attacher cette \u00e9tiquette \u00e0 elle-m\u00eame &#8211; un processus appel\u00e9 auto-ubiquitination. Ce processus la conduit \u00e0 \u00eatre d\u00e9grad\u00e9e, c&#8217;est-\u00e0-dire qu&#8217;il indique \u00e0 la cellule qu&#8217;elle doit se d\u00e9barrasser des niveaux excessifs de cette prot\u00e9ine.<\/p>\n\n\n\n<p>Le groupe Bhogaraju \u00e0 l&#8217;EMBL Grenoble utilise des approches bas\u00e9es sur la biologie structurale et cellulaire pour \u00e9tudier ces m\u00e9canismes impliquant l&#8217;ubiquitine dans la physiologie normale et pathologique. L&#8217;\u00e9quipe, en collaboration avec le<a href=\"https:\/\/www.embl.org\/groups\/hennig\/\"> groupe Hennig<\/a> \u00e0 l&#8217;EMBL Heidelberg, a d\u00e9cid\u00e9 d&#8217;approfondir l&#8217;interaction entre les prot\u00e9ines MAGEA4 et RAD18, en utilisant<a href=\"https:\/\/www.embl.org\/about\/info\/annual-report\/ar2021\/alphafold-a-game-changer-for-structural-biology\"> AlphaFold<\/a>, un outil bas\u00e9 sur l&#8217;intelligence artificielle qui permet aux scientifiques de pr\u00e9dire la structure des prot\u00e9ines.&nbsp;<\/p>\n\n\n\n<p>L\u2019\u00e9quipe, impliquant la doctorante Simonne Griffith-Jones et la postdoctorante Urbi Mukhopadhyay du groupe Bhogaraju, a d\u00e9couvert que MAGEA4 poss\u00e8de un sillon qui peut lier une section de la prot\u00e9ine RAD18, emp\u00eachant cette derni\u00e8re d&#8217;attacher des groupes d&#8217;ubiquitine \u00e0 elle-m\u00eame et d&#8217;\u00eatre ensuite d\u00e9grad\u00e9e.&nbsp;<\/p>\n\n\n\n<p>Autre fait int\u00e9ressant, les chercheurs ont pu utiliser un court fragment de prot\u00e9ine synth\u00e9tique, imitant la partie de RAD18 qui se lie au sillon de MAGEA4, pour bloquer l&#8217;interaction entre les deux prot\u00e9ines. Ceci pourrait ouvrir la voie \u00e0 la conception de m\u00e9dicaments ciblant ce complexe et emp\u00eachant l&#8217;accumulation de RAD18 dans les cellules canc\u00e9reuses.&nbsp;<\/p>\n\n\n\n<p>Les chercheurs ont \u00e9galement trouv\u00e9 un sillon tr\u00e8s similaire dans une autre prot\u00e9ine de la famille MAGE, qui est utilis\u00e9 pour r\u00e9guler une autre prot\u00e9ine favorisant le cancer. Ils pensent que ce sillon pourrait \u00eatre une caract\u00e9ristique g\u00e9n\u00e9rale de la famille MAGE, utilis\u00e9e pour faciliter la liaison aux prot\u00e9ines impliqu\u00e9es dans le d\u00e9veloppement de cancers.<\/p>\n\n\n\n<p>Outre la d\u00e9couverte de ce sillon, les scientifiques ont \u00e9galement observ\u00e9 que deux parties de la prot\u00e9ine RAD18 interagissent entre elles pour lui permettre d\u2019attacher l&#8217;\u00e9tiquette d&#8217;ubiquitine \u00e0 une prot\u00e9ine qui contribue \u00e0 la survie des cellules canc\u00e9reuses. Utilisant des strat\u00e9gies g\u00e9n\u00e9tiques, ils sont parvenus \u00e0 bloquer cette fonction. Ceci indique que de futurs m\u00e9dicaments con\u00e7us pour bloquer cette interaction pourraient potentiellement resensibiliser les cellules canc\u00e9reuses qui ont acquis une r\u00e9sistance aux chimioth\u00e9rapies ou aux radioth\u00e9rapies.<\/p>\n\n\n\n<p>&#8220;Nous sommes ravis de ces donn\u00e9es car nos r\u00e9sultats semblent s&#8217;appliquer \u00e0 de nombreuses prot\u00e9ines MAGE, et ouvrent la voie au ciblage des MAGE qui favorisent le d\u00e9veloppement de cancers&#8221;, a d\u00e9clar\u00e9 Sagar Bhogaraju, chef de groupe \u00e0 l&#8217;EMBL Grenoble, &#8220;Nous travaillons actuellement \u00e0 la mise au point de m\u00e9thodes de criblage de compos\u00e9s capables de se lier \u00e0 ce point critique des MAGE r\u00e9cemment d\u00e9couvert.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"<p>A new study from the Bhogaraju Group at EMBL Grenoble reveals how the cancer-promoting MAGE family of proteins bind to their targets, aiding the development of anti-cancer drugs that target these proteins.<\/p>\n","protected":false},"author":16,"featured_media":66829,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[2,17591],"tags":[789,38,37,35],"embl_taxonomy":[9792],"class_list":["post-66827","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","category-science-technology","tag-bhogaraju","tag-cancer","tag-grenoble","tag-structural-biology","embl_taxonomy-embl-grenoble"],"acf":{"featured":true,"show_featured_image":false,"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"article_intro":"<p>A new study from the Bhogaraju Group at EMBL Grenoble reveals how the cancer-promoting MAGE family of proteins bind to their targets, aiding the development of anti-cancer drugs that target these proteins<\/p>\n","related_links":[{"link_description":"Bhogaraju group","link_url":"https:\/\/www.embl.org\/groups\/bhogaraju\/"}],"source_article":[{"publication_title":"Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins","publication_link":{"title":"","url":"https:\/\/www.embopress.org\/doi\/full\/10.1038\/s44318-024-00058-9","target":"_blank"},"publication_authors":"Griffith-Jones S., et al.","publication_source":"The EMBO Journal","publication_date":"6 March 2024","publication_doi":"10.1038\/s44318-024-00058-9"}],"in_this_article":false,"press_contact":"None","article_translations":[{"translation_language":"Fran\u00e7ais","translation_anchor":"#french"}],"languages":""},"embl_taxonomy_terms":[{"uuid":"a:3:{i:0;s:36:\"b14d3f13-5670-44fb-8970-e54dfd9c921a\";i:1;s:36:\"89e00fee-87f4-482e-a801-4c3548bb6a58\";i:2;s:36:\"8f81131e-d37c-470c-848f-618fce652295\";}","parents":[],"name":["EMBL Grenoble"],"slug":"embl-grenoble","description":"Where &gt; All EMBL sites &gt; EMBL Grenoble"}],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.2 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Studying the relationship between cancer-promoting proteins | EMBL<\/title>\n<meta name=\"description\" content=\"New study reveals how a cancer-promoting family of proteins binds their targets, potentially aiding the development of anti-cancer drugs.\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.embl.org\/news\/science\/studying-the-relationship-between-cancer-promoting-proteins\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Studying the relationship between cancer-promoting proteins | EMBL\" \/>\n<meta property=\"og:description\" content=\"New study reveals how a cancer-promoting family of proteins binds their targets, potentially aiding the development of anti-cancer drugs.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.embl.org\/news\/science\/studying-the-relationship-between-cancer-promoting-proteins\/\" \/>\n<meta property=\"og:site_name\" content=\"EMBL\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/embl.org\/\" \/>\n<meta property=\"article:published_time\" content=\"2024-03-06T10:46:46+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-03-22T10:41:35+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/03\/20240229_Bhogarju_CancerCells_Final_1000x600.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1000\" \/>\n\t<meta property=\"og:image:height\" content=\"600\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Guest author(s)\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:creator\" content=\"@embl\" \/>\n<meta name=\"twitter:site\" content=\"@embl\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Guest author(s)\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"6 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"NewsArticle\",\"@id\":\"https:\/\/www.embl.org\/news\/science\/studying-the-relationship-between-cancer-promoting-proteins\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/studying-the-relationship-between-cancer-promoting-proteins\/\"},\"author\":{\"name\":\"Guest author(s)\",\"@id\":\"https:\/\/www.embl.org\/news\/#\/schema\/person\/b4d9366b2ebe691c4015c64c3619205b\"},\"headline\":\"Studying the relationship between cancer-promoting proteins\",\"datePublished\":\"2024-03-06T10:46:46+00:00\",\"dateModified\":\"2024-03-22T10:41:35+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/studying-the-relationship-between-cancer-promoting-proteins\/\"},\"wordCount\":1338,\"publisher\":{\"@id\":\"https:\/\/www.embl.org\/news\/#organization\"},\"image\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/studying-the-relationship-between-cancer-promoting-proteins\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2024\/03\/20240229_Bhogarju_CancerCells_Final_1000x600.jpg\",\"keywords\":[\"bhogaraju\",\"cancer\",\"grenoble\",\"structural biology\"],\"articleSection\":[\"Science\",\"Science &amp; 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