Inhibition of the chimeric DnaJ-PKAc enzyme by endogenous inhibitor proteins.

Autor: Averill AM; Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, Vermont., Rehman HT; Division of Hematology and Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont.; University of Vermont Cancer Center, Burlington, Vermont., Charles JW; Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont., Dinh TA; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York.; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Danyal K; Department of Pathology, Larner College of Medicine, University of Vermont, Burlington, Vermont., Verschraegen CF; Division of Medical Oncology, The Ohio State Comprehensive Cancer Center, Columbus, Ohio., Stein GS; University of Vermont Cancer Center, Burlington, Vermont.; Department of Biochemistry,, Larner College of Medicine, University of Vermont, Burlington, Vermont., Dostmann WR; Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont., Ramsey JE; University of Vermont Cancer Center, Burlington, Vermont.; Department of Biochemistry,, Larner College of Medicine, University of Vermont, Burlington, Vermont.
Jazyk: angličtina
Zdroj: Journal of cellular biochemistry [J Cell Biochem] 2019 Aug; Vol. 120 (8), pp. 13783-13791. Date of Electronic Publication: 2019 Apr 02.
DOI: 10.1002/jcb.28651
Abstrakt: The chimeric DnaJ-PKAc enzymeresulting from an approximately 400-kb deletion of chromosome 19 is a primary contributor to the oncogenic transformation that occurs in fibrolamellar hepatocellular carcinoma, also called fibrolamellar carcinoma (FLC). This oncogenic deletion juxtaposes exon 1 of the DNAJB1 heat shock protein gene with exon 2 of the PRKACA gene encoding the protein kinase A catalytic subunit, resulting in DnaJ-PKAc fusion under the transcriptional control of the DNAJB1 promoter. The expression of DnaJ-PKAc is approximately 10 times that of wild-type (wt) PKAc catalytic subunits, causing elevated and dysregulated kinase activity that contributes to oncogenic transformation. In normal cells, PKAc activity is regulated by a group of endogenous proteins, termed protein kinase inhibitors (PKI) that competitively inhibit PKAc and assist with the nuclear export of the enzyme. Currently, it is scarcely known whether interactions with PKI are perturbed in DnaJ-PKAc. In this report, we survey existing data sets to assess the expression levels of the various PKI isoforms that exist in humans to identify those that are candidates to encounter DnaJ-PKAc in both normal liver and FLC tumors. We then compare inhibition profiles of wtPKAc and DnaJ-PKAc against PKI and demonstrate that extensive structural homology in the active site clefts of the two enzymes confers similar kinase activities and inhibition by full-length PKI and PKI-derived peptides.
(© 2019 Wiley Periodicals, Inc.)
Databáze: MEDLINE
Externí odkaz: