Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase

The JNK (c-Jun N-terminal kinase)/mitogen-activated protein kinase signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilization and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax (Bcl2-associated X protein) and PUMA (p53 up-regulated modulator of apoptosis). Changes in p73 expression have been linked to tumour progression, particularly in neuroblastomas, whereas in tumours that feature inactivated p53 there is evidence that p73 may mediate the apoptotic response to chemotherapeutic agents. In the present study, we demonstrate a novel link between the JNK signalling pathway and p73. We use pharmacological and genetic approaches to show that JNK is required for p73-mediated apoptosis induced by the DNA damaging agent cisplatin. JNK forms a complex with p73 and phosphorylates it at several serine and threonine residues. The mutation of JNK phosphorylation sites in p73 abrogates cisplatin-induced stabilization of p73 protein, leading to a reduction in p73 transcriptional activity and reduced p73-mediated apoptosis. Our results demonstrate that the JNK pathway is an important regulator of DNA damage-induced apoptosis mediated by p73.

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DNA damage-induced apoptosis and mitogen-activated protein kinase pathway contribute to the toxicity of dronedarone in hepatic cells

Environmental and Molecular Mutagenesis ◽

10.1002/em.22173 ◽

2018 ◽

Vol 59 (4) ◽

pp. 278-289 ◽

Cited By ~ 12

Author(s):

Si Chen ◽

Zhen Ren ◽

Dianke Yu ◽

Baitang Ning ◽

Lei Guo

Keyword(s):

Dna Damage ◽

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Hepatic Cells ◽

Mitogen Activated Protein ◽

Induced Apoptosis ◽

Kinase Pathway

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γ-Tocotrienol-induced apoptosis in human gastric cancer SGC-7901 cells is associated with a suppression in mitogen-activated protein kinase signalling

British Journal Of Nutrition ◽

10.1017/s0007114507879128 ◽

2008 ◽

Vol 99 (6) ◽

pp. 1247-1254 ◽

Cited By ~ 52

Author(s):

Wenguang Sun ◽

Qi Wang ◽

Bingqing Chen ◽

Jiaren Liu ◽

Huikun Liu ◽

...

Keyword(s):

Molecular Mechanisms ◽

Caspase 3 ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

Human Gastric Cancer ◽

Down Regulation ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Human Gastric Adenocarcinoma ◽

Induced Apoptosis

Tocotrienols have been shown to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in tocotrienol-induced apoptosis are still unclear. In the present study, γ-tocotrienol induced apoptosis in human gastric adenocarcinoma SGC-7901 cell line through down regulation of the extracellular signal-regulated kinase (ERK) signalling pathway. Furthermore, γ-tocotrienol-induced apoptosis was accompanied by down regulation of Bcl-2, up regulation of Bax, activation of caspase-3, and subsequent poly (ADP-ribose) polymerase cleavage. These results indicated that up or down regulation of Bcl-2 family proteins play a major role in the initiation of γ-tocotrienol-induced apoptosis as an activator of caspase-3.γ-Tocotrienol also down regulated the activation of the Raf-ERK signalling pathway, and down regulated c-Myc by decreasing the expressions of Raf-1 and p-ERK1/2 proteins. The results suggest that key regulators in tocotrienol-induced apoptosis may be Bcl-2 families and caspase-3 in SGC-7901 cells through down regulation of the Raf-ERK signalling pathway.

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Phospholipase D Elevates the Level of MDM2 and Suppresses DNA Damage-Induced Increases in p53

Molecular and Cellular Biology ◽

10.1128/mcb.24.13.5677-5686.2004 ◽

2004 ◽

Vol 24 (13) ◽

pp. 5677-5686 ◽

Cited By ~ 44

Author(s):

Li Hui ◽

Tarek Abbas ◽

Rafal M. Pielak ◽

Troy Joseph ◽

Jill Bargonetti ◽

...

Keyword(s):

Dna Damage ◽

Phospholipase D ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Mdm2 Expression ◽

Elevated Expression ◽

P53 Response ◽

P53 Activation ◽

Induced Apoptosis ◽

Survival Signals

ABSTRACT Phospholipase D (PLD) has been reported to generate survival signals that prevent apoptosis induced by serum withdrawal. We have now found that elevated expression of PLD also suppresses DNA damage-induced apoptosis. Since DNA damage-induced apoptosis is often mediated by p53, we examined the effect of elevated PLD expression on the regulation of p53 stabilization. We report here that PLD suppresses DNA damage-induced increases in p53 stabilization in cells where PLD has been shown to provide a survival signal. Elevated expression of PLD also led to increased expression of the p53 E3 ubiquitin ligase MDM2 and increased turnover of p53. PLD1-stimulated increases in MDM2 expression and suppression of p53 activation were blocked by inhibition of mTOR and the mitogen-activated protein kinase pathway. Although PLD did not activate the phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway activate the basal levels of PI3K activity were partially required for PLD1-induced increases in MDM2. These data provide evidence that survival signals generated by PLD involve suppression of the p53 response pathway.

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Role of p38 Mitogen-activated Protein Kinase and Caspases in UV-B–induced Apoptosis of Murine Peritoneal Macrophages¶

Photochemistry and Photobiology ◽

10.1562/0031-8655(2004)79<48:ropmpk>2.0.co;2 ◽

2004 ◽

Vol 79 (1) ◽

pp. 48 ◽

Cited By ~ 2

Author(s):

Gautam Sethi ◽

Ajit Sodhi

Keyword(s):

Protein Kinase ◽

Peritoneal Macrophages ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Murine Peritoneal Macrophages ◽

Induced Apoptosis

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Mitogen-Activated Protein Kinase Expression Profiling Revealed Its Role in Regulating Stress Responses in Potato (Solanum tuberosum)

Plants ◽

10.3390/plants10071371 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1371

Author(s):

Madiha Zaynab ◽

Athar Hussain ◽

Yasir Sharif ◽

Mahpara Fatima ◽

Mateen Sajid ◽

...

Keyword(s):

Solanum Tuberosum ◽

Protein Kinase ◽

Stress Responses ◽

Expression Profiling ◽

Regulatory Elements ◽

Mitogen Activated Protein Kinase ◽

High Expression ◽

Primary Data ◽

A Genome ◽

Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) cascades are the universal signal transduction networks that regulate cell growth and development, hormone signaling, and other environmental stresses. However, their essential contribution to plant tolerance is very little known in the potato (Solanum tuberosum) plant. The current study carried out a genome-wide study of StMAPK and provided a deep insight using bioinformatics tools. In addition, the relative expression of StMAPKs was also assessed in different plant tissues. The similarity search results identified a total of 22 StMAPK genes in the potato genome. The sequence alignment also showed conserved motif TEY/TDY in most StMAPKs with conserved docking LHDXXEP sites. The phylogenetic analysis divided all 22 StMAPK genes into five groups, i.e., A, B, C, D, and E, showing some common structural motifs. In addition, most of the StMAPKs were found in a cluster form at the terminal of chromosomes. The promoter analysis predicted several stress-responsive Cis-acting regulatory elements in StMAPK genes. Gene duplication under selection pressure also indicated several purifying and positive selections in StMAPK genes. In potato, StMAPK2, StMAPK6, and StMAPK19 showed a high expression in response to heat stress. Under ABA and IAA treatment, the expression of the total 20 StMAPK genes revealed that ABA and IAA played an essential role in this defense process. The expression profiling and real-time qPCR (RT-qPCR) exhibited their high expression in roots and stems compared to leaves. These results deliver primary data for functional analysis and provide reference data for other important crops.

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Zamzam water protects cancer cells from chemotherapy-induced apoptosis via mitogen-activated protein kinase-dependent pathway

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2019.109376 ◽

2019 ◽

Vol 118 ◽

pp. 109376

Author(s):

Abdul Khalid Siraj ◽

Rafia Begum ◽

Roxanne Melosantos ◽

Wafaa Albalawy ◽

Jehan Abboud ◽

...

Keyword(s):

Protein Kinase ◽

Cancer Cells ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Induced Apoptosis ◽

Dependent Pathway

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UVB-mediated activation of p38 mitogen-activated protein kinase enhances resistance of normal human keratinocytes to apoptosis by stabilizing cytoplasmic p53

Biochemical Journal ◽

10.1042/bj20020072 ◽

2002 ◽

Vol 365 (1) ◽

pp. 133-145 ◽

Cited By ~ 96

Author(s):

Nadine CHOUINARD ◽

Kristoffer VALERIE ◽

Mahmoud ROUABHIA ◽

Jacques HUOT

Keyword(s):

Adaptive Response ◽

Human Keratinocytes ◽

Dominant Negative ◽

Mitogen Activated Protein Kinase ◽

Dominant Negative Mutant ◽

Normal Human Keratinocytes ◽

Mitogen Activated Protein ◽

Normal Human ◽

Induced Apoptosis ◽

Negative Mutant

Human keratinocytes respond to UV rays by developing a fast adaptive response that contributes to maintaining their functions and survival. We investigated the role of the mitogen-activated protein kinase pathways in transducing the UV signals in normal human keratinocytes. We found that UVA, UVB or UVC induced a marked and persistent activation of p38, whereas c-Jun N-terminal kinase or extracellular signal-regulated kinase were less or not activated respectively. Inhibition of p38 activity by expression of a dominant-negative mutant of p38 or with SB203580 impaired cell viability and led to an increase in UVB-induced apoptosis. This sensitization to apoptosis was independent of caspase activities. Inhibition of p38 did not sensitize transformed HaCaT keratinocytes to UVB-induced apoptosis. In normal keratinocytes, expression of a dominant-negative mutant of p53 increased UVB-induced cell death, pointing to a role for p53. In these cells, UVB triggered a p38-dependent phosphorylation of p53 on Ser-15. This phosphorylation was associated with an SB203580-sensitive accumulation of p53, even in the presence of a serine phosphatase inhibitor. Accumulated p53 was localized mainly in the cytoplasm, independently of CRM1 nuclear export. In HaCaT cells, p53 was localized exclusively in the nucleus and its distribution and level were not affected by UVB or p38 inhibition. However, UVB induced an SB203580-insensitive phosphorylation on Ser-15 of mutated p53. Overall, our results suggest that, in normal human keratinocytes, protection against UVB depends on p38-mediated phosphorylation and stabilization of p53 and is tightly associated with the cytoplasmic sequestration of wild-type p53. We conclude that the p38/p53 pathway plays a key role in the adaptive response of normal human keratinocytes against UV stress.

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MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00010.2007 ◽

2007 ◽

Vol 293 (5) ◽

pp. F1556-F1563 ◽

Cited By ~ 44

Author(s):

Frank Y. Ma ◽

Greg H. Tesch ◽

Richard A. Flavell ◽

Roger J. Davis ◽

David J. Nikolic-Paterson

Keyword(s):

Inflammatory Response ◽

P38 Mapk ◽

Renal Injury ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Mrna Levels ◽

Direct Role ◽

Mitogen Activated Protein ◽

Early Inflammatory Response ◽

Induced Apoptosis

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3−/− mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3−/− kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3−/− kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3−/− UUO mice. Furthermore, cultured Mkk3−/− tubular epithelial cells showed resistance to H2O2-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3−/− mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3−/− UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

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