[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-380156-105":59,"doc-detail-380156-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","e3-ligase-mg53-suppresses-tumor-growth-by-degrading-cyclin-d1","E3 ligase MG53 suppresses tumor growth by degrading cyclin D1","","Cyclin D1 is a critical cell-cycle regulator whose aberrant expression drives oncogenesis, including treatment refractoriness associated with impaired ubiquitination-dependent degradation. This study shows that MG53 is downregulated in over 80% of colorectal and gastric tumors versus matched normal tissues, and reduced MG53 links to higher cyclin D1 levels and worse survival. Mechanistically, MG53 catalyzes K48-linked ubiquitination and proteasomal degradation of cyclin D1, inducing G1 arrest and suppressing proliferation and tumor growth. MG53 loss causes cyclin D1 accumulation and accelerates cancer growth in vitro and in vivo, highlighting MG53 as a therapeutic target.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/e3-ligase-mg53-suppresses-tumor-growth-by-degrading-cyclin-d1/380156/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/e3-ligase-mg53-suppresses-tumor-growth-by-degrading-cyclin-d1/380156.png","ImageObject",300,407,{"name":92,"@type":93},"Jake","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main role of cyclin D1 in the cell cycle, and why is it relevant to cancer?","Question",{"text":112,"@type":113},"Cyclin D1 regulates the transition from G1 to S phase. Its dysregulation, often through overexpression or defective degradation, contributes to tumorigenesis and cancer progression.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does MG53 affect cyclin D1 and cell-cycle progression?",{"text":117,"@type":113},"MG53 catalyzes K48-linked ubiquitination followed by cyclin D1 degradation. This promotes G1 cell-cycle arrest and suppresses cancer cell proliferation.",{"name":119,"@type":110,"acceptedAnswer":120},"What evidence supports MG53 as a tumor suppressor in vivo and in patients?",{"text":121,"@type":113},"In colorectal and gastric cancer patients, MG53 is downregulated in most tumors and correlates with increased cyclin D1 abundance and poorer survival. MG53 deficiency leads to cyclin D1 accumulation and faster cancer growth in culture and animal models.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},380156,1790330321,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":41},962084928904,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Signal Transduction [and Targeted Therapy](and Targeted Therapy www.nature.com/sigtrans)[ www.nature.com/sigtrans](and Targeted Therapy www.nature.com/sigtrans)  \nE3 ligase MG53 suppresses tumor growth by degrading cyclin D1  \nMeng Fang1,2, Hong-Kun Wu3,4, Yumeng Pei 1,2, Yan Zhang1,5, Xiangyu Gao6, Yanyun He1,2, Gengjia Chen 1, Fengxiang Lv 1,5, Peng Jiang 1, Yumei Li1, Wenwen Li1, Peng Jiang7, Lin Wang8, Jiafu Ji6 ✉, Xinli Hu 1,5 ✉ and Rui-Ping Xiao1,2,5 ✉  \nDue to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1 . Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.  \nSignal Transduction and Targeted Therapy (2023)8:263 ; [https://doi.org/10.1038/s41392-023-01458-9](https://doi.org/10.1038/s41392-023-01458-9)  \nINTRODUCTION  \nCyclin D1 plays multiple roles in tumorigenesis, including enabling cell cycle progression, promoting cell migration, facilitating DNA damage repair, and driving chromosome instability.1 The oncogenic effect of cyclin D1 can be attributed to mutations in its coding region, but is more often associated with cyclin D1 overexpression.2,3 The elevation in cyclin D1 level can be caused by genetic rearrangements,4,5 gene duplication,6,7 transcriptional upregulation,8–10 or aberrant degradation.11, 12 In particular, the degradation of cyclin D1 is dictated by its polyubiquitination in normal cell cycle when the protein level of cyclin D1 fluctuates at different stages. The expression of cyclin D1 is induced by mitogenic stimulations. Then cyclin D1 enters nucleus and couples with CDK4/6 to inactivate retinoblastoma tumor suppressor (Rb) by phosphorylation, which enables the transcription of E2Fdependent genes. When cells enter S phase, cyclin D1 is phosphorylated and transported back to cytosol where it is ubiquitinated followed by degradation via proteasome. In addition, various stress conditions, such as radiation, DNA damage, drug treatment, or starvation, may also induce cyclin D1 degradation and subsequent cell cycle exit.13  \nEmerging evidence has pinpointed a pivotal role of dysfunctional E3 ubiquitin ligase in the cancer-associated cyclin D1 accumulation. Moreover, recent studies have implicated  \ndysfunction in ubiquitination-dependent degradation of cyclin D1 as a key mechanism underlying insensitivity towards CDK4/6 inhibitors (CDK4/6is) in treating certain types of cancers.14–16 Thus, innate insensitivity or acquired resistance to CDK4/6is constitutes a major hindrance in the clinical application of these drugs. To date, two large E3 ligase complexes, S-phase kinase-associated protein 1-Cullin 1-F-box complex (SCF) and anaphase-promoting complex/cyclosome (APC/C), have been reported to mediate the degradation-related polyubiquitination of cyclin D1 .1 SCF E3 ubiquit","cbCaiv5ANFBZit7H","https://ap.wps.com/l/cbCaiv5ANFBZit7H","pdf",5552048,12,"English","# Introduction\n## Cyclin D1 in tumorigenesis and cell-cycle regulation\n## Ubiquitination-dependent cyclin D1 degradation and E3 ligases\n## Therapeutic relevance to CDK4/6 inhibitor sensitivity","[{\"question\":\"What is the main role of cyclin D1 in the cell cycle, and why is it relevant to cancer?\",\"answer\":\"Cyclin D1 regulates the transition from G1 to S phase. Its dysregulation, often through overexpression or defective degradation, contributes to tumorigenesis and cancer progression.\"},{\"question\":\"How does MG53 affect cyclin D1 and cell-cycle progression?\",\"answer\":\"MG53 catalyzes K48-linked ubiquitination followed by cyclin D1 degradation. This promotes G1 cell-cycle arrest and suppresses cancer cell proliferation.\"},{\"question\":\"What evidence supports MG53 as a tumor suppressor in vivo and in patients?\",\"answer\":\"In colorectal and gastric cancer patients, MG53 is downregulated in most tumors and correlates with increased cyclin D1 abundance and poorer survival. MG53 deficiency leads to cyclin D1 accumulation and faster cancer growth in culture and animal models.\"}]","E3 ligase MG53 suppresses tumor growth by degrading cyclin D1 | PDF",1790239048]