title: Oncogenic Ras and B-Raf proteins positively regulate death receptor 5 expression through co-activation of ERK and JNK signaling.
abstract: Oncogenic mutations of ras and B-raf frequently occur in many cancer types and are critical for cell transformation and tumorigenesis. Death receptor 5 (DR5) is a cell surface pro-apoptotic death receptor for tumor necrosis factor-related apoptosis-inducing ligand and has been targeted in cancer therapy. The current study has demonstrated induction of DR5 expression by the oncogenic proteins Ras and B-Raf and revealed the underlying mechanisms. We demonstrated that both Ras and B-Raf induce DR5 expression by enforced expression of oncogenic Ras (e.g. H-Ras12V or K-Ras12V) or B-Raf (i.e. V600E) in cells and by analyzing gene expression array data generated from cancer cell lines and from human cancer tissues. This finding is further supported by our results that knockdown of endogenous K-Ras or B-Raf (V600E) reduced the expression of DR5. Importantly, we have elucidated that Ras induces DR5 expression through co-activation of ERK/RSK and JNK signaling pathways and subsequent cooperative effects among the transcriptional factors CHOP, Elk1, and c-Jun to enhance DR5 gene transcription. Moreover, we found that the majority of cancer cell lines highly sensitive to the DR5 agonistic antibody AMG655 have either Ras or B-Raf mutations. Our findings warrant further study on the biology of DR5 regulation by Ras and B-Raf, which may provide new insight into the biology of Ras and B-Raf, and on the potential impact of Ras or B-Raf mutations on the outcome of DR5-targeted cancer therapy.
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia 30322.
authors: You-Take
authors: YT
authors: Oh
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia 30322.
authors: Ping
authors: P
authors: Yue
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia 30322.
authors: Wei
authors: W
authors: Zhou
authors: Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232.
authors: Justin M
authors: JM
authors: Balko
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536.
authors: Esther P
authors: EP
authors: Black
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia 30322.
authors: Taofeek K
authors: TK
authors: Owonikoko
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia 30322.
authors: Fadlo R
authors: FR
authors: Khuri
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia 30322. Electronic address: ssun@emory.edu.
authors: Shi-Yong
authors: SY
authors: Sun
mesh_terms: D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000276:immunology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C497249:DDIT3 protein, human; C494112:ELK1 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D050807:ets-Domain Protein Elk-1; D051742:Transcription Factor CHOP; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D018631:ras Proteins