Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell death.
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Kukkonen-Macchi A, Sicora O, Kaczynska K, Oetken-Lindholm C, Pouwels J, Laine L, Kallio MJ
Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell death.
J Cell Sci. 2011 Jan 15;124(Pt 2):216-27. doi: 10.1242/jcs.068254. Epub 2010 Dec 15.
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- 21172807 [ View in PubMed]
- Abstract
The p38 mitogen-activated protein kinase (p38 MAPK) family, which is comprised of four protein isoforms, p38alpha, p38beta, p38gamma and p38delta, 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 p38gamma MAPK as a modulator of mitotic progression and mitotic cell death. In HeLa cells, loss of p38gamma results in multipolar spindle formation and chromosome misalignment, which induce a transient M phase arrest. The majority of p38gamma-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, p38gamma 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 p38gamma prevents chromosomal instability and supports mitotic cell viability.