Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

Anu Kukkonen-Macchi, Oana Sicora, Katarzyna Kaczynska, Christina Oetken-Lindholm, Jeroen Pouwels, Leena Laine, Marko Kallio

Research output: Contribution to journalArticleScientificpeer-review

23 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)216-227
JournalJournal of Cell Science
Volume124
Issue number2
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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p38 Mitogen-Activated Protein Kinases
Cell Death
Kinetochores
Cell Division
Spindle Poles
Chromosomal Instability
HeLa Cells
Mitosis
Cell Differentiation
Cell Survival
Cell Cycle
Protein Isoforms
Phosphotransferases
Chromosomes
Inflammation
Growth

Keywords

  • p38 MAPK
  • p38{gamma}
  • Mitosis
  • Cell death
  • Kinetochore

Cite this

Kukkonen-Macchi, A., Sicora, O., Kaczynska, K., Oetken-Lindholm, C., Pouwels, J., Laine, L., & Kallio, M. (2011). Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death. Journal of Cell Science, 124(2), 216-227. https://doi.org/10.1242/jcs.068254
Kukkonen-Macchi, Anu ; Sicora, Oana ; Kaczynska, Katarzyna ; Oetken-Lindholm, Christina ; Pouwels, Jeroen ; Laine, Leena ; Kallio, Marko. / Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death. In: Journal of Cell Science. 2011 ; Vol. 124, No. 2. pp. 216-227.
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Kukkonen-Macchi, A, Sicora, O, Kaczynska, K, Oetken-Lindholm, C, Pouwels, J, Laine, L & Kallio, M 2011, 'Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death', Journal of Cell Science, vol. 124, no. 2, pp. 216-227. https://doi.org/10.1242/jcs.068254

Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death. / Kukkonen-Macchi, Anu; Sicora, Oana; Kaczynska, Katarzyna; Oetken-Lindholm, Christina; Pouwels, Jeroen; Laine, Leena; Kallio, Marko.

In: Journal of Cell Science, Vol. 124, No. 2, 2011, p. 216-227.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Kukkonen-Macchi, Anu

AU - Sicora, Oana

AU - Kaczynska, Katarzyna

AU - Oetken-Lindholm, Christina

AU - Pouwels, Jeroen

AU - Laine, Leena

AU - Kallio, Marko

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AB - 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.

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Kukkonen-Macchi A, Sicora O, Kaczynska K, Oetken-Lindholm C, Pouwels J, Laine L et al. Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death. Journal of Cell Science. 2011;124(2):216-227. https://doi.org/10.1242/jcs.068254