Comparative Analysis of Two Gene-Targeting Approaches Challenges the Tumor-Suppressive Role of the Protein Kinase MK5-PRAKReport as inadecuate




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MK5 MAPK-activated protein kinase 5 or PRAK p38-regulated and -activated kinase are alternative names for a serine-threonine protein kinase downstream to ERK3-4 and p38 MAPK. A previous gene targeting approach for MK5-PRAK termed here MK5-PRAK-Δex8 revealed a seemingly tumor-suppressive role of MK5-PRAK in DMBA-induced one step skin carcinogenesis and Ras-induced transformation. Here we demonstrate that an alternative targeting strategy of MK5-PRAK termed MK5-PRAK-Δex6 increased neither tumor incidence in the one step skin carcinogenesis model, nor Ras-induced transformation in primary cells. Interestingly, due to the targeting strategies and exon skipping both knockouts do not completely abolish the generation of MK5-PRAK protein, but express MK5-PRAK deletion mutants with different biochemical properties depending on the exon targeted: Targeting of exon 6 leads to expression of an unstable cytoplasmic catalytically inactive MK5-PRAK-Δex6 mutant while targeting of exon 8 results in a more stable nuclear MK5-PRAK-Δex8 mutant with residual catalytic activity. The different properties of the MK5-PRAK deletion mutants could be responsible for the observed discrepancy between the knockout strains and challenge the role of MK5-PRAK in p53-dependent tumor suppression. Further MK5-PRAK knockout and knock-in mouse strains will be necessary to assign a physiological function to MK5-PRAK in this model organism.



Author: Natalia Ronkina, Claus Johansen, Lisa Bohlmann, Juri Lafera, Manoj B. Menon, Christopher Tiedje, Kathrin Laaß, Benjamin E. Turk,

Source: http://plos.srce.hr/



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