{"id":{"repo_id":"nus","oai_identifier":"oai:scholarbank.nus.edu.sg:10635/236517"},"canonical_url":"https://search.dev.ndltd.org/etd/nus/oai:scholarbank.nus.edu.sg:10635/236517","repository":{"repo_id":"nus","name":"National University of Singapore","base_url":"https://scholarbank.nus.edu.sg/oai/request"},"display":{"title":"INTERPLAY BETWEEN MDM2 AND TFAM REGULATES OXIDATIVE PHOSPHORYLATION IN DRUG-RESISTANT ONCOGENE-ADDICTED CANCERS","abstract":"Tyrosine kinase inhibitors (TKI) remain the first-line treatment for most oncogene-addicted cancers. However, prolonged exposure to TKI could lead to development of resistance. There is mounting evidence of OXPHOS dependency as a mechanism of TKI resistance, but the cause of this metabolic switch remains elusive. Here, we report a novel mechanism involving mitochondria-bound MDM2 (mtMDM2) in driving OXPHOS regulation in TKI-resistant cancers through an interaction with TFAM. This phenomenon involves the mitochondrial-cytoplasm shuttling of MDM2 in a p53-independent manner, which leads to enhanced mitochondrial biogenesis via TFAM transcriptional machinery. Furthermore, we describe an increase in AKT signalling in TKI-resistant cancers that contributed to protein stability of MDM2 through phosphorylation. Inhibition of AKT leads to decrease in MDM2 Ser166 phosphorylation and increase mitochondria localisation in TKI-resistant cells. Collectively, we describe a novel observation that altered metabolism and TKI resistance in cancer cells could be mediated by MDM2 phosphorylation and mitochondria localization.","abstract_html":"Tyrosine kinase inhibitors (TKI) remain the first-line treatment for most oncogene-addicted cancers. However, prolonged exposure to TKI could lead to development of resistance. There is mounting evidence of OXPHOS dependency as a mechanism of TKI resistance, but the cause of this metabolic switch remains elusive. Here, we report a novel mechanism involving mitochondria-bound MDM2 (mtMDM2) in driving OXPHOS regulation in TKI-resistant cancers through an interaction with TFAM. This phenomenon involves the mitochondrial-cytoplasm shuttling of MDM2 in a p53-independent manner, which leads to enhanced mitochondrial biogenesis via TFAM transcriptional machinery. Furthermore, we describe an increase in AKT signalling in TKI-resistant cancers that contributed to protein stability of MDM2 through phosphorylation. Inhibition of AKT leads to decrease in MDM2 Ser166 phosphorylation and increase mitochondria localisation in TKI-resistant cells. Collectively, we describe a novel observation that altered metabolism and TKI resistance in cancer cells could be mediated by MDM2 phosphorylation and mitochondria localization.","abstract_has_math":false,"creators":["EU JIE QING"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-08-03","date_published":"2022-08-03","updated_at":"2026-07-24T03:31:00Z","subjects":["mdm2; metabolism; drug resistance; tfam; oncogene addicted"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["EU JIE QING"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2022-08-03"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://scholarbank.nus.edu.sg/handle/10635/236517"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["mdm2; metabolism; drug resistance; tfam; oncogene addicted"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://scholarbank.nus.edu.sg/bitstreams/2536697c-4b91-48c1-9215-1980638d96fc/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Tyrosine kinase inhibitors (TKI) remain the first-line treatment for most oncogene-addicted cancers. However, prolonged exposure to TKI could lead to development of resistance. There is mounting evidence of OXPHOS dependency as a mechanism of TKI resistance, but the cause of this metabolic switch remains elusive. Here, we report a novel mechanism involving mitochondria-bound MDM2 (mtMDM2) in driving OXPHOS regulation in TKI-resistant cancers through an interaction with TFAM. This phenomenon involves the mitochondrial-cytoplasm shuttling of MDM2 in a p53-independent manner, which leads to enhanced mitochondrial biogenesis via TFAM transcriptional machinery. Furthermore, we describe an increase in AKT signalling in TKI-resistant cancers that contributed to protein stability of MDM2 through phosphorylation. Inhibition of AKT leads to decrease in MDM2 Ser166 phosphorylation and increase mitochondria localisation in TKI-resistant cells. Collectively, we describe a novel observation that altered metabolism and TKI resistance in cancer cells could be mediated by MDM2 phosphorylation and mitochondria localization."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["cd3add605e98e133af96b88d54d1bc40","177d2fdf22fb6364bc2c56c28b263d16"]},{"key":"dc:title","label":"Title","values":["INTERPLAY BETWEEN MDM2 AND TFAM REGULATES OXIDATIVE PHOSPHORYLATION IN DRUG-RESISTANT ONCOGENE-ADDICTED CANCERS"]}]}],"canonical_facts":{"dc:creator":["EU JIE QING"],"dc:date.issued":["2022-08-03"],"dc:description.abstract":["Tyrosine kinase inhibitors (TKI) remain the first-line treatment for most oncogene-addicted cancers. However, prolonged exposure to TKI could lead to development of resistance. There is mounting evidence of OXPHOS dependency as a mechanism of TKI resistance, but the cause of this metabolic switch remains elusive. Here, we report a novel mechanism involving mitochondria-bound MDM2 (mtMDM2) in driving OXPHOS regulation in TKI-resistant cancers through an interaction with TFAM. This phenomenon involves the mitochondrial-cytoplasm shuttling of MDM2 in a p53-independent manner, which leads to enhanced mitochondrial biogenesis via TFAM transcriptional machinery. Furthermore, we describe an increase in AKT signalling in TKI-resistant cancers that contributed to protein stability of MDM2 through phosphorylation. Inhibition of AKT leads to decrease in MDM2 Ser166 phosphorylation and increase mitochondria localisation in TKI-resistant cells. Collectively, we describe a novel observation that altered metabolism and TKI resistance in cancer cells could be mediated by MDM2 phosphorylation and mitochondria localization."],"dc:format.checksum.md5":["cd3add605e98e133af96b88d54d1bc40","177d2fdf22fb6364bc2c56c28b263d16"],"dc:identifier.uri":["https://scholarbank.nus.edu.sg/bitstreams/2536697c-4b91-48c1-9215-1980638d96fc/download"],"dc:relation.isreferencedby":["https://scholarbank.nus.edu.sg/handle/10635/236517"],"dc:subject":["mdm2; metabolism; drug resistance; tfam; oncogene addicted"],"dc:title":["INTERPLAY BETWEEN MDM2 AND TFAM REGULATES OXIDATIVE PHOSPHORYLATION IN DRUG-RESISTANT ONCOGENE-ADDICTED CANCERS"],"dc:type":["Thesis"]},"updated_at":"2026-07-24T03:31:00Z"}