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

Abstract

SummaryThe p38 mitogen-activated protein kinase (p38 MAPK) family, which is comprised of four protein isoforms, p38, p38, p38 and p38, 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 p38 MAPK as a modulator of mitotic progression and mitotic cell death. In HeLa cells, loss of p38 results in multipolar spindle formation and chromosome misalignment, which induce a transient M phase arrest. The majority of p38-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, p38 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 p38 prevents chromosomal instability and supports mitotic cell viability.

p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

“…In response to Ras signaling, p38␣ phosphorylation is increased, and phosphorylated p38␣ then functions as a tumor suppressor in vitro (12,13) and in vivo (14,15), whereas p38␥ expression is increased, and resulting p38␥ in turn promotes the oncogenic process independently of (16 -18) and dependent on phosphorylation (19,20). In stress response, although p38␥ is similarly activated as pro-apoptotic p38␣, it plays an anti-apoptotic role under certain conditions (17,(21)(22)(23)(24). Among MAPK family proteins, p38␥ is the only member whose expression is induced during differentiation (25), transformation, and/or invasion (16,18,19).…”

Is p38γ MAPK a metastasis-promoting gene or an oncogenic property-maintaining gene?

“…Our observation revealed that p38γ MAPK knockdown in 4T1 cells led to significant decrease of cell proliferation, a phenomenon also observed in Hela cells. 5 Concomitantly, we observed decreased cell migration and invasion in 4T1 cell with p38γ MAPK depletion. Furthermore, a xenografting experiment showed a significant shrinkage of tumor formation along with marked decrease of lung metastasis, suggesting that the decreased cell migration and invasion or metastasis is mostly due to the effect of p38γ MAPK on cell survival.…”

Stimuli-responsive hybrid nanocarriers developed by controllable integration of hyperbranched PEI with mesoporous silica nanoparticles for sustained intracellular siRNA delivery

“…The AllStars Hs Cell Death Control siRNA is used as a positive transfection. [41][42][43][44][45] A total of 25,000 MDA-MB-231 cells were added to two 24-well plates; one 24-well plate each for long-term monitoring of colony growth by live cell imaging with IncuCyte ZOOM ® (Essen Instruments, Ann Arbor, MI, USA).…”

“…The employed cell-killing siRNA has been used previously as a positive control for transfection. [41][42][43][44][45] The aim of the experiment was to investigate transfection efficiency of MSN nanocarriers in MDA-MB-231 cells; therefore, we used a very general siRNA transfection approach rather than selecting some specific cellular target. The transfection efficacy was benchmarked against a commercial transfection agent, Lipofectamine RNAiMax, as a positive (cell death) control.…”

“…The amount of burst release was suppressed by adding a capping layer of PEI, as was also observed in our earlier study; albeit in which case, the capping layer consisted of PEG chains, which do not promote endosomal escape of cargo. 15,44,45 In polycation-based polymer nanocarriers, the molar ratio of amines in the polymer backbone to phosphates in the nucleic acid (N/P ratio) determines the maximum payload of cargo. A high N/P ratio of 4.5-135 may thus be associated with a risk of toxicity induced by the amines.…”