Alvin Kunyao Guo1, Yoko Itahana1, Veerabrahma Pratap Seshachalam2, Hui Ying Chow3, Sujoy Ghosh2, Koji Itahana4. 1. Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. 2. Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. 3. School of Applied Science, Temasek Polytechnic, 21 Tampines Avenue 1, Singapore, 529757, Singapore. 4. Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. koji.itahana@duke-nus.edu.sg.
Abstract
BACKGROUND: Mutant TP53 interacts with other proteins to produce gain-of-function properties that contribute to cancer metastasis. However, the underlying mechanisms are still not fully understood. METHODS: Using immunoprecipitation and proximity ligation assays, we evaluated breast cancer anti-estrogen resistance 1 (BCAR1) as a novel binding partner of TP53R273H, a TP53 mutant frequently found in human cancers. The biological functions of their binding were examined by the transwell invasion assay. Clinical outcome of patients was analysed based on TP53 status and BCAR1 expression using public database. RESULTS: We discovered a novel interaction between TP53R273H and BCAR1. We found that BCAR1 translocates from the cytoplasm into the nucleus and binds to TP53R273H in a manner dependent on SRC family kinases (SFKs), which are known to enhance metastasis. The expression of full-length TP53R273H, but not the BCAR1 binding-deficient mutant TP53R273HΔ102-207, promoted cancer cell invasion. Furthermore, among the patients with mutant TP53, high BCAR1 expression was associated with a poorer prognosis. CONCLUSIONS: The interaction between TP53R273H and BCAR1 plays an important role in enhancing cancer cell invasion. Thus, our study suggests a disruption of the TP53R273H-BCAR1 binding as a potential therapeutic approach for TP53R273H-harbouring cancer patients.
BACKGROUND: Mutant TP53 interacts with other proteins to produce gain-of-function properties that contribute to cancer metastasis. However, the underlying mechanisms are still not fully understood. METHODS: Using immunoprecipitation and proximity ligation assays, we evaluated breast cancer anti-estrogen resistance 1 (BCAR1) as a novel binding partner of TP53R273H, a TP53 mutant frequently found in humancancers. The biological functions of their binding were examined by the transwell invasion assay. Clinical outcome of patients was analysed based on TP53 status and BCAR1 expression using public database. RESULTS: We discovered a novel interaction between TP53R273H and BCAR1. We found that BCAR1 translocates from the cytoplasm into the nucleus and binds to TP53R273H in a manner dependent on SRC family kinases (SFKs), which are known to enhance metastasis. The expression of full-length TP53R273H, but not the BCAR1 binding-deficient mutant TP53R273HΔ102-207, promoted cancer cell invasion. Furthermore, among the patients with mutant TP53, high BCAR1 expression was associated with a poorer prognosis. CONCLUSIONS: The interaction between TP53R273H and BCAR1 plays an important role in enhancing cancer cell invasion. Thus, our study suggests a disruption of the TP53R273H-BCAR1 binding as a potential therapeutic approach for TP53R273H-harbouring cancerpatients.
Authors: Jiajun Zhu; Morgan A Sammons; Greg Donahue; Zhixun Dou; Masoud Vedadi; Matthäus Getlik; Dalia Barsyte-Lovejoy; Rima Al-awar; Bryson W Katona; Ali Shilatifard; Jing Huang; Xianxin Hua; Cheryl H Arrowsmith; Shelley L Berger Journal: Nature Date: 2015-09-02 Impact factor: 49.962
Authors: Dattatreya Mellacheruvu; Zachary Wright; Amber L Couzens; Jean-Philippe Lambert; Nicole A St-Denis; Tuo Li; Yana V Miteva; Simon Hauri; Mihaela E Sardiu; Teck Yew Low; Vincentius A Halim; Richard D Bagshaw; Nina C Hubner; Abdallah Al-Hakim; Annie Bouchard; Denis Faubert; Damian Fermin; Wade H Dunham; Marilyn Goudreault; Zhen-Yuan Lin; Beatriz Gonzalez Badillo; Tony Pawson; Daniel Durocher; Benoit Coulombe; Ruedi Aebersold; Giulio Superti-Furga; Jacques Colinge; Albert J R Heck; Hyungwon Choi; Matthias Gstaiger; Shabaz Mohammed; Ileana M Cristea; Keiryn L Bennett; Mike P Washburn; Brian Raught; Rob M Ewing; Anne-Claude Gingras; Alexey I Nesvizhskii Journal: Nat Methods Date: 2013-07-07 Impact factor: 28.547