The Transcriptional Activator Mirk/Dyrk1B Is Sequestered by p38α/β MAP Kinase

摘要: Abstract Mirk/Dyrk1B protein kinase was shown in an earlier study to function as a transcriptional activator of HNF1α, which Mirk phosphorylates at Ser249 within its CREB (cAMP-response element-binding protein)-binding (CBP) binding domain (1). The MAPK MKK3 also activate kinase, implicating the biological response certain stress agents. Another substrate, p38MAPK, is now inhibit kinase-independent manner. Co-immunoprecipitation experiments demonstrated that kinase-inactive p38AF, well wild-type p38, sequestered and prevented association with MKK3. Only p38α p38β isoforms, but not γ or δ complexed Mirk. p38αMAPK blocked activation HNF1α dose-dependent manner, high levels p38αAF completely suppressing activity Size fractionation by fast liquid chromatography on Superdex 200 found monomer vivo, 150–700 kDa subnuclear complexes, co-migrate nuclear body scaffolding PML. Endogenous Mirk, 500–700-kDa accumulate when export leptomycin B. Stable overexpression increases fraction p38 these 500–700 suggesting complexes act depots for p38. Sequestration may occur complexes. Synchronization fluctuate about 10-fold cell cycle, while do not, leading speculation endogenous could only block were low S phase elevated G0/G1. These data suggest novel cycle-dependent suppression cells are proliferating, thus limiting growth-arrested cells.