Induction of Apoptosis by SB202190 through Inhibition of p38β Mitogen-activated Protein Kinase

Nemoto, Shino; Xiang, Jialing; Huang, Shuang; Lin, Anning

doi:10.1074/jbc.273.26.16415

Cited by 266 publications

(234 citation statements)

References 58 publications

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“…p38g and SAPK4 were shown to phosphorylate predominantly transcription factors such as ATF-2 and were less e ective in phosphorylating MAPKAPK2 Goedert et al, 1997;Kumar et al, 1997). In addition, it has been reported that SB202190 was a speci®c inhibitor of p38a and p38b (Nemoto et al, 1998). Our study indicated that SB202190 signi®cantly suppressed UVB induced phosphorylation of MAPKAPK2, which implied that p38g and SAPK4 might play relatively less important roles compared to other p38 family members for UVB induced c-fos expression.…”

Section: Discussionmentioning

confidence: 55%

Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes

Chen

Bowden

1999

Oncogene

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The e ects of p38 MAP kinase and ERK on UVB induced c-fos gene expression were studied in a human keratinocyte cell line, FL30. UVB signi®cantly increased c-fos gene expression at both the transcriptional and protein levels. p38 and ERK were also signi®cantly activated after UVB irradiation. Treating the cells with p38 inhibitor SB202190 inhibited p38 activation, but not ERK; treating the cells with MEK-1 inhibitor PD98059 inhibited ERK activation without suppressing p38 activation. The kinase activation was determined by Western blots using phospho-p38 or ERK antibodies, or an in vivo p38 activity assay. Further studies demonstrated that blocking p38 almost completely abrogated UVB induced c-fos gene transcription and c-Fos protein synthesis. Inhibiting ERK partially abrogated UVB induced c-fos transcriptional and protein levels. Suppression of both p38 and ERK not only completely blocked UVB induced c-fos expression, but also decreased c-fos gene basal expression. Our data indicated that p38 may play a more important role than ERK in UVB induced cfos expression in human keratinocytes. Since c-fos expression may play an important role in UVB induced AP-1 activation, and AP-1 activation is known to play a role in tumor promotion, both p38 and ERK could be potential targets for chemoprevention of skin cancer.

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Section: Discussionmentioning

confidence: 55%

Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes

Chen

Bowden

1999

Oncogene

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“…Historically, sustained activation of p38MAPK is associated with apoptosis and conversely inhibition rescues cells from apoptotic death (Chang and Karin 2001;Mansouri et al 2003;Cai et al 2006;Zhou et al 2006;Tanel and Averill-Bates 2007). It should be noted that SB202190 inhibits both p38α and p38β and that p38α is pro-apoptotic whereas p38β MAPK isoform may be associated with activation of pro-survival pathways (Nemoto et al 1998). Indeed, a recent study by Caughlan et al (2004) demonstrated that CPF activates p38 MAPK and that SB202190 accelerates CPF-induced toxicity in cortical neurons.…”

Section: Discussionmentioning

confidence: 99%

Characterization of chlorpyrifos-induced apoptosis in placental cells

Saulsbury¹,

Heyliger²,

Wang³

et al. 2008

Toxicology

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The mechanism by which chlorpyrifos exerts its toxicity in fetal and perinatal animals has yet to be elucidated. Since the placenta is responsible for transport of nutrients and is a major supplier hormones to the fetus, exposure to xenobiotics that alter the function or viability of placenta cells could ostensibly alter the development of the fetus. In this study, JAR cells were used to determine if CPF and the metabolites 3,5,6-trichloro-2-pyridinol (TCP) and chlorpyrifos-oxon (CPO) are toxic to the placenta. Our results indicate that chlorpyrifos (CPF), and its metabolite chlorpyrifos-oxon (CPO) caused a dose-dependent reduction in cellular viability with CPF being more toxic than its metabolites. Chlorpyrifos-induced toxicity was characterized by the loss of mitochondrial potential, the appearance of nuclear condensation and fragmentation, down-regulation of Bcl-2 as well as upregulation of TNFα and FAS mRNA. Pharmacological inhibition of FAS, nicotinic and TNF-α receptors did not attenuate CPF-induced toxicity. Atropine exhibited minimal ability to reverse toxicity. Furthermore, signal transduction inhibitors PD98059, SP600125, LY294002 and U0126 failed to attenuate toxicity; however, SB202190 (inhibitor of p38α and p38β MAPK) sensitized cells to CPF-induced toxicity. Pan-caspase inhibitor Q-VD-OPh produced a slight but significant reversal of CPF-induced toxicity indicating that the major caspase pathways are not integral to CPF-induced toxicity. Taken collectively, these results suggest that chlorpyrifos induces apoptosis in placental cells through pathways not dependent on FAS/TNF signaling, activation of caspases or inhibition of cholinesterase. In addition, our data further indicates that activation of p38 MAPK is integral to the protection cells against CPF-induced injury.

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“…At least four p38 subfamilies (α, β, γ and δ) have been isolated. P38-α induces, while p38-β suppresses cell death [36]. SB203580 inhibits mainly α and β isoforms [37,38].…”

Section: Discussionmentioning

confidence: 99%

Differential phosphorylation of mitogen-activated protein kinase families by epidermal growth factor and ultraviolet B irradiation in SV40-transformed human keratinocytes

Takahashi

Kinouchi

Manabe

et al. 2001

Journal of Dermatological Science

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ELSEVIER, Nakamura, S; Takahashi, H; Kinouchi, M; Manabe, A; Ishida-Yamamoto, A; Hashimoto, Y; Iizuka, H, JOURNAL OF DERMATOLOGICAL SCIENCE, 25(2), 139-149, 2001. authorSV-40 transformed human keratinocytes (SVHK cells) were stimulated with epidermal growth factor (EGF)2 and ultraviolet B (UVB) irradiation. Following the stimulation, cell growth, apoptosis, and the activities of mitogen-activated protein (MAP) kinase families were analyzed. EGF (100ng/ml) increased SVHK cell number compared with control cells cultured in serum-free DMEM medium. The EGF-stimulated cells did not show DNA fragmentation. In contrast, UVB irradiation (40mJ/cm2) markedly decreased viable cell number, that was accompanied with DNA fragmentation. EGF stimulated extracellular signal-regulated kinase (ERK) and stress-activated protein kinase/c-Jun N-terminal kinase (JNK). Following the EGF stimulation, phosphorylated ERK and JNK were detected by phospho-p42/44 MAP kinase antibody and phospho-SAPK/JNK antibody, respectively. On the other hand, UVB irradiation stimulated the phosphorylation of p38 and JNK but not of ERK. The stimulation of ERK and JNK induced by EGF was observed earlier than the stimulation of p38 and JNK induced by UVB. PD98059, a specific MAP kinase kinase (MAPKK) 1 (also referred to as MEK1) inhibitor, inhibited EGF-dependent cell proliferation, that was associated with the inhibition of ERK and JNK phosphorylation. In contrast, UVB-induced overall cell death was not significantly affected by PD98059, that inhibited phosphorylation of JNK but not of p38. PD98059, however, significantly augmented UVB-induced cell death earlier time points (30min - 2 h). These results indicate that ERK and JNK are activated following EGF stimulation, that might be associated with cell proliferation. On the other hand, UVB-induced apoptosis seems to be mostly associated with the activation of p38. JNK stimulation might provide an anti-apoptotic tonus during the UVB-induced, p38-associated SVHK cell death

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Induction of Apoptosis by SB202190 through Inhibition of p38β Mitogen-activated Protein Kinase

Cited by 266 publications

References 58 publications

Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes

Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes

Characterization of chlorpyrifos-induced apoptosis in placental cells

Differential phosphorylation of mitogen-activated protein kinase families by epidermal growth factor and ultraviolet B irradiation in SV40-transformed human keratinocytes

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