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postgraduate thesis: CRL4Cop1 : a glucose-responsive E3 ligase targeting P53 for tumor development
Title | CRL4Cop1 : a glucose-responsive E3 ligase targeting P53 for tumor development |
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Authors | |
Issue Date | 2023 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Luo, Y. [骆怡帆]. (2023). CRL4Cop1 : a glucose-responsive E3 ligase targeting P53 for tumor development. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | According to the famous “Warburg effect”, Cancer cells are addicted to glucose and heavily require glucose for energy generation via glycolysis. Clinical evidences show the disorders of glucose metabolism, especially hyperglycemia, which is the common feature of diabetes and obesity, promote cancer development in human. However, such epidemiological association between non-hereditary cancer development and glycometabolic disorders remains under-explained. It is well-known that pro-tumorigenic metabolism is critically inhibited by famous tumor suppressor Tumor Protein 53 (P53) at transcriptional level. In this study, a glucose-responsive signaling axis is delineated in which glucose degrades p53 to reinforce glucose uptake and glycolysis via transcriptional regulation, thereby constituting a self-amplifying loop by which glucose metabolism overturns tumor suppression. P53 was first identified as the potential transcriptional regulator for glucose self-regulation by RNA-seq screening to inhibit glucose uptake and glycolysis. Following studies also unravel that COP1 and Cullin RING ligase 4 (CRL4) together act as the E3 ligase mediating glucose-induced p53 ubiquitylation and degradation. Glucose also enhances the activity of CRL4COP1 by promoting the assembly of CRL4 with its substrate receptor COP1. Moreover, this glucose-responsive p53 degradation can be reversed by the neddylation inhibitors (MLN4924/NAcM-OPT) or COP1-p53 binding inhibitory peptide (p28), suggesting that CRL4COP1 can be a targetable vulnerability for overnutrition-associated cancer. By elucidating how glucose autonomously up-regulates self-metabolism via p53 in cancer cells, this study not only reveals the glucose-sensing function of CRL4COP1 activated by glucose for tumor development, but could also provide potential therapeutic targets for drug development and cancer treatment. Additionally, by extending our findings to pancreatic beta cells, a glucose-responsive ETV5 degradation for insulin secretion by CRL4COP1 is also found, indicating CRL4COP1 as the possible therapeutic targets for diabetes patient. These results together suggest CRL4COP1 as the general glucose-responsive E3 ligase in mammalians to ubiquitylate and degrade key transcription factors to achieve the functions of different organs. |
Degree | Doctor of Philosophy |
Subject | Cancer Glucose Ligases p53 protein |
Dept/Program | Biological Sciences |
Persistent Identifier | http://hdl.handle.net/10722/336487 |
DC Field | Value | Language |
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dc.contributor.author | Luo, Yifan | - |
dc.contributor.author | 骆怡帆 | - |
dc.date.accessioned | 2024-01-31T10:55:13Z | - |
dc.date.available | 2024-01-31T10:55:13Z | - |
dc.date.issued | 2023 | - |
dc.identifier.citation | Luo, Y. [骆怡帆]. (2023). CRL4Cop1 : a glucose-responsive E3 ligase targeting P53 for tumor development. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/336487 | - |
dc.description.abstract | According to the famous “Warburg effect”, Cancer cells are addicted to glucose and heavily require glucose for energy generation via glycolysis. Clinical evidences show the disorders of glucose metabolism, especially hyperglycemia, which is the common feature of diabetes and obesity, promote cancer development in human. However, such epidemiological association between non-hereditary cancer development and glycometabolic disorders remains under-explained. It is well-known that pro-tumorigenic metabolism is critically inhibited by famous tumor suppressor Tumor Protein 53 (P53) at transcriptional level. In this study, a glucose-responsive signaling axis is delineated in which glucose degrades p53 to reinforce glucose uptake and glycolysis via transcriptional regulation, thereby constituting a self-amplifying loop by which glucose metabolism overturns tumor suppression. P53 was first identified as the potential transcriptional regulator for glucose self-regulation by RNA-seq screening to inhibit glucose uptake and glycolysis. Following studies also unravel that COP1 and Cullin RING ligase 4 (CRL4) together act as the E3 ligase mediating glucose-induced p53 ubiquitylation and degradation. Glucose also enhances the activity of CRL4COP1 by promoting the assembly of CRL4 with its substrate receptor COP1. Moreover, this glucose-responsive p53 degradation can be reversed by the neddylation inhibitors (MLN4924/NAcM-OPT) or COP1-p53 binding inhibitory peptide (p28), suggesting that CRL4COP1 can be a targetable vulnerability for overnutrition-associated cancer. By elucidating how glucose autonomously up-regulates self-metabolism via p53 in cancer cells, this study not only reveals the glucose-sensing function of CRL4COP1 activated by glucose for tumor development, but could also provide potential therapeutic targets for drug development and cancer treatment. Additionally, by extending our findings to pancreatic beta cells, a glucose-responsive ETV5 degradation for insulin secretion by CRL4COP1 is also found, indicating CRL4COP1 as the possible therapeutic targets for diabetes patient. These results together suggest CRL4COP1 as the general glucose-responsive E3 ligase in mammalians to ubiquitylate and degrade key transcription factors to achieve the functions of different organs. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Cancer | - |
dc.subject.lcsh | Glucose | - |
dc.subject.lcsh | Ligases | - |
dc.subject.lcsh | p53 protein | - |
dc.title | CRL4Cop1 : a glucose-responsive E3 ligase targeting P53 for tumor development | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biological Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2023 | - |
dc.identifier.mmsid | 991044634604803414 | - |