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|Title:||INVESTIGATING NOVEL MECHANISMS OF MAPK PATHWAY REGULATION IN MELANOMA||Authors:||AZAD SAEI||ORCID iD:||orcid.org/0000-0002-1000-2953||Keywords:||USP28, Melanoma, Vemurafenib, BRAF, FBXW7, Rigosertib||Issue Date:||3-Aug-2018||Citation:||AZAD SAEI (2018-08-03). INVESTIGATING NOVEL MECHANISMS OF MAPK PATHWAY REGULATION IN MELANOMA. ScholarBank@NUS Repository.||Abstract:||Mitogen activated protein kinase (MAPK) pathway plays a crucial role in maintaining cellular homeostasis. However, deregulation of its components has been demonstrated to lead to various malignant phenotypes. Moreover, the mechanism of ubiquitination in controlling various protein functions such as stabilization cannot be neglected. In order to investigate the role of deubiquitinating enzymes (DUBs) involved MAPK pathway regulation, a RNAi screen was performed targeting all known human DUBs. Here I demonstrated that the deubiquitinating enzyme USP28 functions to destabilize BRAF. Importantly, in this study we demonstrated that USP28 is deleted in a proportion of melanoma patients and loss of USP28 conferred resistance to vemurafenib in melanoma models in vitro and in vivo. Hence, the loss of USP28 may act as a biomarker for response to BRAF inhibitor therapy in these patients. Furthermore, we identified a known PLK1 inhibitor, rigosertib, as a possible therapeutic strategy for targeting USP28-depleted tumors.||URI:||http://scholarbank.nus.edu.sg/handle/10635/150888|
|Appears in Collections:||Ph.D Theses (Open)|
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