title: Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell death.
abstract: The p38 mitogen-activated protein kinase (p38 MAPK) family, which is comprised of four protein isoforms, p38α, p38β, p38γ and p38δ, forms one of the key MAPK pathways. The p38 MAPKs are implicated in many cellular processes including inflammation, differentiation, cell growth, cell cycle and cell death. The function of p38 MAPKs in mitotic entry has been well established, but their role in mitotic progression has remained controversial. We identify p38γ MAPK as a modulator of mitotic progression and mitotic cell death. In HeLa cells, loss of p38γ results in multipolar spindle formation and chromosome misalignment, which induce a transient M phase arrest. The majority of p38γ-depleted cells die at mitotic arrest or soon after abnormal exit from M-phase. We show that p38 MAPKs are activated at the kinetochores and spindle poles throughout mitosis by kinase(s) that are stably bound to these structures. Finally, p38γ is required for the normal kinetochore localization of polo-like kinase 1 (Plk1), and this contributes to the activity of the p38 MAPK pathway. Our data suggest a link between mitotic regulation and the p38 MAPK pathway, in which p38γ prevents chromosomal instability and supports mitotic cell viability.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, 20521 Turku, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Kukkonen-Macchi
authors.forename: Oana
authors.initials: O
authors.lastname: Sicora
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kaczynska
authors.forename: Christina
authors.initials: C
authors.lastname: Oetken-Lindholm
authors.forename: Jeroen
authors.initials: J
authors.lastname: Pouwels
authors.forename: Leena
authors.initials: L
authors.lastname: Laine
authors.forename: Marko J
authors.initials: MJ
authors.lastname: Kallio
mesh_terms: D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002477:Cells / Q000166:cytology* / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D048291:Mitogen-Activated Protein Kinase 12 / Q000172:deficiency* / Q000235:genetics; D008938:Mitosis; D008941:Spindle Apparatus / Q000201:enzymology
chemical_list: D048291:Mitogen-Activated Protein Kinase 12