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      Structure and Function of Human DnaJ Homologue Subfamily A Member 1 (DNAJA1) and Its Relationship to Pancreatic Cancer

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          Abstract

          Pancreatic cancer has a dismal 5 year survival rate of 5.5% that has not been improved over the past 25 years despite an enormous amount of effort. Thus, there is an urgent need to identify truly novel yet druggable protein targets for drug discovery. The human protein DnaJ homologue subfamily A member 1 (DNAJA1) was previously shown to be downregulated 5-fold in pancreatic cancer cells and has been targeted as a biomarker for pancreatic cancer, but little is known about the specific biological function for DNAJA1 or the other members of the DnaJ family encoded in the human genome. Our results suggest the overexpression of DNAJA1 suppresses the stress response capabilities of the oncogenic transcription factor, c-Jun, and results in the diminution of cell survival. DNAJA1 likely activates a DnaK protein by forming a complex that suppresses the JNK pathway, the hyperphosphorylation of c-Jun, and the anti-apoptosis state found in pancreatic cancer cells. A high-quality nuclear magnetic resonance solution structure of the J-domain of DNAJA1 combined with a bioinformatics analysis and a ligand affinity screen identifies a potential DnaK binding site, which is also predicted to overlap with an inhibitory binding site, suggesting DNAJA1 activity is highly regulated.

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                Author and article information

                Journal
                Biochemistry
                Biochemistry
                bi
                bichaw
                Biochemistry
                American Chemical Society
                0006-2960
                1520-4995
                10 February 2015
                10 February 2014
                04 March 2014
                : 53
                : 8
                : 1360-1372
                Affiliations
                []Department of Chemistry, University of Nebraska—Lincoln , Lincoln, Nebraska 68588, United States
                [2] Eppley Institute for Research in Cancer and Allied Diseases, §Department of Biochemistry and Molecular Biology, Department of Genetics, Cell Biology and Anatomy, and Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States
                [# ]Department of Molecular Biology and Biochemistry, Center for Advanced Biotechnology and Medicine, Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854, United States
                [@ ]Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854, United States
                Author notes
                [* ]Department of Chemistry, 722 Hamilton Hall, University of Nebraska—Lincoln, Lincoln, NE 68588-0304. E-mail: rpowers3@ 123456unl.edu . Telephone: (402) 472-3039. Fax: (402) 472-9402.
                Article
                10.1021/bi401329a
                3985919
                24512202
                de0938a9-e814-4057-8713-f17ec076036a
                Copyright © 2014 American Chemical Society
                History
                : 26 September 2013
                : 10 February 2014
                Funding
                National Institutes of Health, United States
                Categories
                Article
                Custom metadata
                bi401329a
                bi-2013-01329a

                Biochemistry
                Biochemistry

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