Structure and function of human DnaJ homologue subfamily A member 1 (DNAJA1) and its relationship to pancreatic cancer

Jaime L. Stark, Kamiya Mehla, Nina Chaika, Thomas B. Acton, Rong Xiao, Pankaj Singh, Gaetano T. Montelione, Robert Powers

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1360-1372
Number of pages13
JournalBiochemistry
Volume53
Issue number8
DOIs
StatePublished - Mar 4 2014

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Pancreatic Neoplasms
Cells
HSP40 Heat-Shock Proteins
Binding Sites
Biomarkers
Bioinformatics
MAP Kinase Signaling System
Proteins
Human Genome
Transcription Factors
Drug Discovery
Genes
Computational Biology
Nuclear magnetic resonance
Apoptosis
Ligands
Cell Survival
Magnetic Resonance Spectroscopy
Down-Regulation
Survival Rate

ASJC Scopus subject areas

  • Biochemistry

Cite this

Structure and function of human DnaJ homologue subfamily A member 1 (DNAJA1) and its relationship to pancreatic cancer. / Stark, Jaime L.; Mehla, Kamiya; Chaika, Nina; Acton, Thomas B.; Xiao, Rong; Singh, Pankaj; Montelione, Gaetano T.; Powers, Robert.

In: Biochemistry, Vol. 53, No. 8, 04.03.2014, p. 1360-1372.

Research output: Contribution to journalArticle

Stark, Jaime L. ; Mehla, Kamiya ; Chaika, Nina ; Acton, Thomas B. ; Xiao, Rong ; Singh, Pankaj ; Montelione, Gaetano T. ; Powers, Robert. / Structure and function of human DnaJ homologue subfamily A member 1 (DNAJA1) and its relationship to pancreatic cancer. In: Biochemistry. 2014 ; Vol. 53, No. 8. pp. 1360-1372.
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