Osmotic Shock Induces G1 Arrest through p53 Phosphorylation at Ser33 by Activated p38MAPK without Phosphorylation at Ser15 and Ser20

Kishi, Hiroto; Nakagawa, Kazumi; Matsumoto, Mitsuhiro; Suga, Moritaka; Ando, Masashi; Taya, Yoichi; Yamaizumi, Masaru

doi:10.1074/jbc.m105134200

Cited by 121 publications

(91 citation statements)

References 51 publications

(83 reference statements)

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“…p38-MAPK is involved in cellular response to UVinduced DNA damage and DNA replication inhibition, leading to p53 phosphorylation at Ser15, 37, and 46 (29), and has been suggested to indirectly (through activation of CK2) phosphorylate p53 at Ser392 (31-33). p38-MAPK was also reported to phosphorylate p53 at Ser33 during osmotic shock (30). However, based on the recent report in the literature (48), we cannot exclude other kinases from being involved in phosphorylation of p53 Ser392 in response to inhibition of T-type Ca 2þ channels.…”

Section: Discussionmentioning

confidence: 82%

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

Dziegielewska

Brautigan

Larner

et al. 2014

Molecular Cancer Research

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Epithelial tumor cells express T-type Ca 2þ channels, which are thought to promote cell proliferation. This study investigated the cellular response to T-type Ca 2þ channel inhibition either by small-molecule antagonists or by RNAi-mediated knockdown. Selective T-type Ca 2þ channel antagonists caused growth inhibition and apoptosis more effectively in HCT116 cells expressing wild-type p53 (p53wt), than in HCT116 mutant p53 À/À cells. These antagonists increased p53-dependent gene expression and increased genomic occupancy of p53 at specific target sequences. The knockdown of a single T-type Ca 2þ channel subunit (CACNA1G) reduced cell growth and induced caspase-3/7 activation in HCT116 p53wt cells as compared with HCT116 mutant p53 À/À cells. Moreover, CaCo2 cells that do not express functional p53 were made more sensitive to CACNA1G knockdown when p53wt was stably expressed. Upon T-type Ca 2þ channel inhibition, p38-MAPK promoted phosphorylation at Ser392 of p53wt. Cells treated with the inhibitor SB203580 or specific RNAi targeting p38-MAPKa/b (MAPK14/MAPK11) showed resistance to T-type Ca 2þ channel inhibition. Finally, the decreased sensitivity to channel inhibition was associated with decreased accumulation of p53 and decreased expression of p53 target genes, p21Cip1 (CDKN1A) and BCL2-binding component 3 (BBC3/PUMA).

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Section: Discussionmentioning

confidence: 82%

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

Dziegielewska

Brautigan

Larner

et al. 2014

Molecular Cancer Research

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“…We identified two serine residues, serine 15 and serine 33, that are remarkably phosphorylated by rpS3 knockdown (Figure 2b). These data lead to the speculation that the p38-dependent phosphorylation is involved in the p53 induction, since it has been demonstrated previously that the phosphorylation at these sites is regulated mainly by p38 kinase (Bulavin et al, 1999;Lavin and Gueven, 2006), and has an effect on the stability and activity of p53 (Bulavin et al, 1999;Kishi et al, 2001).…”

Section: Rps3-knockdown Exhibits Aberrant Ribosome Biogenesismentioning

confidence: 89%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

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“…p38 MAPK is an important regulator of cell cycle and survival in CLL, possibly through direct interaction with, and phosphorylation of p53 at specific serine sites. 33 p38 MAPK activation by IL-24 and other factors, such as TGF-b, 34 may also contribute to anergy in CLL similarly to that demonstrated in T cells. 35 Since Mda-7 promoted cell survival, it could be expected that its expression level correlates with the clinical/biological status in CLL, and a quantitative study of Mda-7 and phospho-p38 MAPK should be carried out, although in preliminary studies we failed to observe a difference between Ig-mutated vs unmutated patients.…”

Section: Discussionmentioning

confidence: 99%

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

et al. 2006

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Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/ IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.

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Osmotic Shock Induces G1 Arrest through p53 Phosphorylation at Ser33 by Activated p38MAPK without Phosphorylation at Ser15 and Ser20

Cited by 121 publications

References 51 publications

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

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