Stress-induced immediate-early gene, egr-1, involves activation of p38/JNK1

Lim, Cheh Peng; Jain, Neeraj; Cao, Xinmin

doi:10.1038/sj.onc.1201834

Cited by 151 publications

(117 citation statements)

References 36 publications

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“…5A) . These characteristics of the activation of JNK and p38 are quite similar to those that were reported when mouse fibroblast NIH3T3 cells were treated with sodium arsenite (Lim et al, 1998). In contrast to the marked activation of JNK and p38, we observed a decrease in the levels of the activated forms of ERK 1/2 upon treatment of the cells with As 2 O 3 (Fig.…”

Section: Effect On Cell Cycle Phase Distribution It Was Recentlysupporting

confidence: 38%

Arsenic Trioxide Induces Apoptosis in Chronic Myelogenous Leukemia K562 Cells:Possible Involvement of p38 MAP Kinase

Shim¹,

Kim²,

Yang³

et al. 2002

BMB Reports

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Arsenic trioxide (As 2 O 3 ) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As 2 O 3 might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As 2 O 3 to induce apoptosis in K562 cells. In vitro cytotoxicity of As 2 O 3 was evaluated in K562 cells by a MTT assay; the IC 50 value for As 2 O 3 was determined to be 10 µM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 µM As 2 O 3 for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 µM As 2 O 3 by a Western blot analysis. Next, we examined the MAP kinasesignaling pathway of As 2 O 3 -induced apoptosis in K562 cells. As 2 O 3 at 10 µM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As 2 O 3 induced apoptotic cell death. These results suggest that As 2 O 3 is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.

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Section: Effect On Cell Cycle Phase Distribution It Was Recentlysupporting

confidence: 38%

Arsenic Trioxide Induces Apoptosis in Chronic Myelogenous Leukemia K562 Cells:Possible Involvement of p38 MAP Kinase

Shim¹,

Kim²,

Yang³

et al. 2002

BMB Reports

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“…It was reported previously that arsenite caused the activation of both JNK and p38 but did not affect ERK in HeLa cells 42 and in NIH 3T3 cells. 36 When pheochromocytoma PC12 cells were treated with arsenite, JNK was activated, but ERK activity was unchanged. 17 In fibroblast Rat-1 cells and PC12 cells, 400 M of sodium arsenite activated ERK, JNK and p38.…”

Section: Discussionmentioning

confidence: 99%

“…These characteristics of the activation of JNK and p38 are quite similar to those reported when mouse fibroblast NIH3T3 cells are treated with sodium arsenite. 36 To examine whether activation of p38 by As 2 O 3 might be associated with the induction of apoptosis in U937 cells, we treated cells with As 2 O 3 in the presence of SB203580, a specific inhibitor of p38. As shown in Figure 6, As 2 O 3 -induced apoptosis in U937 cells was significantly inhibited by addition of 25 M SB203580, as determined by staining of nuclei with Hoechst 33342.…”

Section: Effects On the Map Kinase Cascadementioning

confidence: 99%

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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“…Tumor-bearing mice with average tumor size of approximately 250 mm 3 were randomized into four groups: intratumoral injection (i.t.) of Ad.Egr.TNF (2 Â 10 8 plaque-forming units per 10 ml) with intraperitoneal (i.p.)…”

Section: In Vitro Luciferase Reporter Assaymentioning

confidence: 99%

“…[1][2][3] Ionizing radiation (IR) as well as DNA-damaging chemotherapeutic agents readily induce the Egr-1 promoter via the CArG elements. [4][5][6][7] This regulation is exploited in the replication-deficient adenoviral gene therapy vector Ad.Egr.TNF (TNFerade Biologic, GenVec Inc., Gaithersburg, MD), in which the pro-apoptotic cytokine tumor necrosis factor a (TNF-a), under control of CArG elements, is induced by radio-and/or chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol is an effective inducer of CArG-driven TNF-α gene therapy

et al. 2007

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We report the anticarcinogenic, anti-aging polyphenol resveratrol activates the radio-and chemo-inducible cancer gene therapy vector Ad.Egr.TNF, a replication-deficient adenovirus that expresses human tumor necrosis factor a (TNF-a) under control of the Egr-1 promoter. Like ionizing radiation or chemotherapeutic agents previously shown to activate Ad.Egr.TNF, resveratrol also induces Egr-1 expression from its chromosomal locus with a possible role for Egr-1 promoter CC(A þ T)richGG sequences in the expression of TNF-a. Resveratrol induction of TNF-a in Ad.Egr.TNF-infected tumor xenografts demonstrated antitumor response in human and rat tumor models comparable to that of radio-or chemotherapy-induced TNF-a. Although sirtuins are known targets of resveratrol, in vitro inhibition of SIRT1 activity did not abrogate resveratrol induction of Egr-1 expression. This suggests that SIRT1 is not essential to mediate resveratrol induction of Egr-1. Nevertheless, control of transgene expression via resveratrol activation of Egr-1 may extend use of Ad.Egr.TNF to patients intolerant of radiation or cytotoxic therapy and offer a novel tool for development of other inducible gene therapies.

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Stress-induced immediate-early gene, egr-1, involves activation of p38/JNK1

Cited by 151 publications

References 36 publications

Arsenic Trioxide Induces Apoptosis in Chronic Myelogenous Leukemia K562 Cells:Possible Involvement of p38 MAP Kinase

Arsenic Trioxide Induces Apoptosis in Chronic Myelogenous Leukemia K562 Cells:Possible Involvement of p38 MAP Kinase

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

Resveratrol is an effective inducer of CArG-driven TNF-α gene therapy

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