Novel Homologues of CSBP/p38 MAP Kinase: Activation, Substrate Specificity and Sensitivity to Inhibition by Pyridinyl Imidazoles

Kumar, Sanjay; McDonnell, Peter; Gum, Rebecca J.; Hand, Annalisa T.; Lee, John C.; Young, Peter R.

doi:10.1006/bbrc.1997.6849

Cited by 468 publications

(313 citation statements)

References 37 publications

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“…It has been demonstrated that a few p38 subtypes such as p38g and SAPK4 were resistant to pyridinyl-imidazole type of p38 inhibitor. 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).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…These p38 MAP kinases named p38g or SAPK 3 and SAPK 4 also di er at least to some extent in their stimulus dependent activation and their substrate speci®city e.g. SAPK 3 and SAPK 4 phosphorylate predominantly transcription factors such as ATF-2 and Elk-1 and are far less e ective in phosphorylating MAPKAP kinase-2 Goedert et al, 1997;Kumar et al, 1997). It is possible that the p38 MAP kinase form with decreased phosphorylation represents the SB 203580 sensitive group of p38 whereas the p38 MAP kinase form with increased phosphorylation represents the resistant group of p38.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p38 MAP kinase increases okadaic acid mediated AP-1 expression and DNA binding but has no effect on TRE dependent transcription

1999

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By performing in vitro kinase assays we found in papilloma producing 308 mouse keratinocytes that okadaic acid elevated activities of extracellular signalregulated kinase (ERK) 1/2, c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases (MAPKs). This okadaic acid mediated activation of MAP kinases correlated with increased AP-1 binding to a consensus TPA responsive element (TRE) and elevated TRE dependent transcription. To determine the role of p38 MAP kinases in these processes we employed the speci®c p38 MAP kinase inhibitor SB 203580. Using orthophosphate labeling we showed a decrease in phosphorylation of MAPK activated protein kinase-2 (MAPKAP-K2) indicating reduced activity of p38 MAPKs utilizing this kinase as substrate. In contrast, we found that SB 203580 raised activities of ERK-1/2 and JNKs. Electrophoretic mobility shift assays revealed an increase in TRE binding activity in response to SB 203580 most likely resulting from increased expression of the major TRE binding components JunD and FosB as indicated by Western blot analyses. Increased TRE DNA binding failed to lead to increased transactivation correlating with the inability of SB 203580 to increase phosphorylation of these AP-1 proteins. These data indicate that SB 203580 sensitive p38 MAP kinases are not involved in okadaic acid mediated increases in TRE DNA binding and transactivation.

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“…p38 cDNA was also cloned as a molecule that binds puridinyl imidazole derivatives which are known to inhibit biosynthesis of inflammatory cytokines such as interleukin-1 (IL-1) and tumor-necrosis factor (TNF) in LPS stimulated monocytes [4]. To date, four splice variants of the p38 family have been identified: p38α, p38β [5], p38γ (ERK6, SAPK3) [6,7], and p38δ (SAPK4) [8,9]. Of these, p38 and p38β are ubiquitously expressed while p38γ and p38δ are differentially expressed depending on tissue type.…”

Section: Properties Of P38 Map Kinase Membersmentioning

confidence: 99%

Activation and signaling of the p38 MAP kinase pathway

2005

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The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

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Novel Homologues of CSBP/p38 MAP Kinase: Activation, Substrate Specificity and Sensitivity to Inhibition by Pyridinyl Imidazoles

Cited by 468 publications

References 37 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

Inhibition of p38 MAP kinase increases okadaic acid mediated AP-1 expression and DNA binding but has no effect on TRE dependent transcription

Activation and signaling of the p38 MAP kinase pathway

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