The Stress Inducer Arsenite Activates Mitogen-activated Protein Kinases Extracellular Signal-regulated Kinases 1 and 2 via a MAPK Kinase 6/p38-dependent Pathway

Ludwig, Stephan; Hoffmeyer, Angelika; Goebeler, Matthias; Kilian, Karin; Häfner, Heide; Neufeld, Bernd; Han, Jiahuai; Rapp, Ulf R.

doi:10.1074/jbc.273.4.1917

Cited by 198 publications

(162 citation statements)

References 26 publications

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“…The results shown are representative of three independent experiments p38 MAPK and AP-1 expression, binding and transactivation SF Rosenberger et al of p38 MAP kinase upregulates JNK activity. A similar interconnection between the di erent MAP kinase cascades has been demonstrated by Ludwig et al (1998) who found that arsenite induced activation of ERK-1/2 is mediated by p38 MAP kinase. The ability of MAP kinases to regulate the activity of their family members may be explained by their e ects on activating kinases and/or deactivating phosphatases as documented by the ®nding that p38 MAP kinase is involved in inhibition of the ERK-1/2 activating kinase MEK-1 in response to high concentrations of pervanadate (Daum et al, 1998).…”

Section: Discussionsupporting

confidence: 73%

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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Section: Discussionsupporting

confidence: 73%

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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“…43 A higher concentration, 500 M, of sodium arsenite also activated ERK1 and ERK2 in a p38-dependent manner during transformation of human HEK293 embryonic kidney cells. 44 This is, to our knowledge, the first report of the rapid inactivation of ERK1 and ERK2 by As 2 O 3 . Furthermore, MEK1 and MEK2, which act upstream of ERK, were also inactivated when U937 cells were treated with As 2 O 3 .…”

Section: Discussionmentioning

confidence: 61%

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

2001

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The mechanism of the induction of apoptosis by arsenic trioxide (As 2 O 3 ), which was demonstrated recently to be an effective inducer of apoptosis in patients with leukemia, was examined in detail in human leukemia U937 cells. Upon treatment of U937 cells with 50 M of As 2 O 3 , complete inactivation of the kinases ERK1 and ERK2 was detected within 30 min. p38 was activated within 3 hr, and the maximum activity was detected at 6 hr, when DNA fragmentation remained undetectable. Experiments with transfected cells that expressed constitutively activated MEK1 and a specific inhibitor of p38 also suggested that inactivation of ERKs and activation of p38 might be associated with the induction of apoptosis by As 2 O 3 . In contrast to the inactivation of ERKs and the activation of p38, activation of JNK by Key words: arsenic trioxide; apoptosis; leukemia cells; superoxide; tumorArsenic has long been used in traditional Chinese medicine. Arsenic trioxide (As 2 O 3 ) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) and in patients with APL in whom all-trans-retinoic acid (ATRA) and conventional chemotherapy has failed. 1-4 Studies in vitro indicate that As 2 O 3 can induce apoptosis in myeloma cell lines, in plasma cells from myeloma patients, 5 in malignant lymphocytic cell lines 6,7 as well as primary cultures of lymphocytic leukemia and lymphoma cells, 6 in myeloid and B-cell leukemia cell lines, 8 in megakaryocytic leukemia cell lines, 9 in neuroblastoma cell lines 10 and in HPV16-immortalized human cervical epithelial cells. 11 The mechanism responsible for the induction of apoptosis has not been fully characterized, but As 2 O 3 induced apoptosis in NB4 cells, cloned from a relapsed patient with APL, by inducing loss of PML/RAR␣ protein 12 and by suppressing expression of the Bcl-2 protein. 13 Apoptosis induced by As 2 O 3 and by the organic arsenical melarsoprol in myeloid leukemia cell lines, such as the HL-60, KG-1 and U937 cell lines, was found, however, to be independent of the level of expression of PML and PML-RAR␣. 14 In contrast to its apparent curative effects, As 2 O 3 is known to be a carcinogen in human organs, such as skin and lung, and it has serious side effects such as fluid retention in patients. 15 Other chronic side effects include polyneuropathy, palmar keratosis and skin hyperpigmentation. 15 It is, therefore, desirable to develop other drugs that act by a similar mechanism to that of As 2 O 3 but lack the side effect. While the mechanism of the induction of apoptosis in tumor cells by As 2 O 3 is not well understood, As 2 O 3 has been used to mimic the effects of heat shock on cells. 16 When rat fibroblastic 3Y1 cells and rat PC12 cells are treated with As 2 O 3 , stress-induced kinases such as c-Jun N-terminal kinase (JNK) and p38 are activated. 17 To clarify the mechanism of induction of apoptosis in tumor cells by As 2 O 3 , we examined the effects of As 2 O 3 on the activities of mitogen-activated protein (M...

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“…There appears to be a reasonably linear relationship between the degree of oxidative stress, the formation of disul®de species and the induction of stress responsive proteins. Thioredoxin has been the best characterized cysteine-rich redoxresponsive protein implicated in the regulation of several stress responsive proteins via direct or intermediate interactions (reviewed in Schulze-Ostho et al, 1995; Sen and Packer, 1996; Flohe et al, 1997; Kuo et al, 1995Cavigelli et al, 1996Ludwig et al, 1998Kilk et al, 1996Lim et al, 1997Duhe et al, 1998Krejsa et al, 1997Kang et al, 1998Lui et al, 1998 Piette et al, 1997). The recent identi®cation of thioredoxin as an inhibitor of stress kinase ASK1 (Saitoh et al, 1998), has shed new light on the modes of redox regulatable stress response.…”

Section: Ros-induced Modi®cation Of Redox Sensitive Proteins Which Rementioning

confidence: 99%

Role of redox potential and reactive oxygen species in stress signaling

et al. 1999

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Stress-activated signaling cascades are a ected by altered redox potential. Key contributors to altered redox potential are reactive oxygen species (ROS) which are formed, in most cases, by exogenous genotoxic agents including irradiation, in¯ammatory cytokines and chemical carcinogens. ROS and altered redox potential can be considered as the primary intracellular changes which regulate protein kinases, thereby serving as an important cellular component linking external stimuli with signal transduction in stress response. The mechanisms, which underlie the ROS-mediated response, involve direct alteration of kinases and transcription factors, and indirect modulation of cysteine-rich redox-sensitive proteins exempli®ed by thioredoxin and glutathione Stransferase. This review summarizes the current understanding of the mechanisms contributing to ROS-related changes in key stress activated signaling cascades.

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The Stress Inducer Arsenite Activates Mitogen-activated Protein Kinases Extracellular Signal-regulated Kinases 1 and 2 via a MAPK Kinase 6/p38-dependent Pathway

Cited by 198 publications

References 26 publications

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

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

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

Role of redox potential and reactive oxygen species in stress signaling

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