Activation of MEK Kinase 1 by the c-Abl Protein Tyrosine Kinase in Response to DNA Damage

Kharbanda, Surender; Pandey, Pramod; Yamauchi, Takenori; Kumar, Swagat; Kaneki, Masao; Kumar, Vijay; Bharti, Ajit; Yuan, Zhi Min; Ghanem, Louis; Rana, Ajay; Weichselbaum, Ralph R.; Johnson, Gary L.; Küfe, Donald

doi:10.1128/mcb.20.14.4979-4989.2000

Cited by 83 publications

(59 citation statements)

References 78 publications

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“…In fact, cisplatin induces apoptosis of OHCs in the organ of Corti explants (Kopke et al 1997) and in vivo (Alam et al 2000;Watanabe et al 2002). It is also known that the cytotoxic effects of cisplatin occur via at least two major mechanisms, including the formation of DNA adducts (Huang et al 2000;Kartalou and Essigmann 2001;Kharbanda et al 2000) and damage because of the production of ROS (Evans and Halliwell 1999;Feghali et al 2001;Kopke et al 1997). These processes ultimately cause cell death by apoptosis or necrosis (Davis et al 2001;Jordan and Carmo-Fonseca 2000).…”

Section: Discussionmentioning

confidence: 99%

Cisplatin Cytotoxicity of Auditory Cells Requires Secretions of Proinflammatory Cytokines via Activation of ERK and NF-κB

Kim

Lee

et al. 2007

JARO

219

211

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The ototoxicity of cisplatin, a widely used chemotherapeutic agent, involves a number of mechanisms, including perturbation of redox status, increase in lipid peroxidation, and formation of DNA adducts. In this study, we demonstrate that cisplatin increased the early immediate release and de novo synthesis of proinflammatory cytokines, including TNF-a, IL-1b, and IL-6, through the activation of ERK and NF-kB in HEI-OC1 cells, which are conditionally immortalized cochlear cells that express hair cell markers. Both neutralization of proinflammatory cytokines and pharmacologic inhibition of ERK significantly attenuated the death of HEI-OC1 auditory cells caused by cisplatin and proinflammatory cytokines. We also observed a significant increase in the protein and mRNA levels of proinflammatory cytokines in both serum and cochleae of cisplatin-injected rats, which was suppressed by intraperitoneal injection of etanercept, an inhibitor of TNF-a. Immunohistochemical studies revealed that TNF-a expression was mainly located in the spiral ligament, spiral limbus, and the organ of Corti in the cochleae of cisplatin-injected rats. NF-kB protein expression, which overlapped with terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling-positive signal, was very strong in specific regions of the cochleae, including the organ of Corti, spiral ligament, and stria vascularis. These results indicate that proinflammatory cytokines, especially TNF-a, play a central role in the pathophysiology of sensory hair cell damage caused by cisplatin.

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Section: Discussionmentioning

confidence: 99%

Cisplatin Cytotoxicity of Auditory Cells Requires Secretions of Proinflammatory Cytokines via Activation of ERK and NF-κB

Kim

Lee

et al. 2007

JARO

219

211

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“…19 Ototoxicity following cisplatin therapy is common, and is a result of damage to OHCs of the organ of Corti. 20,21 In fact, cisplatin It is also well known that cytotoxicity of cisplatin occurs via at least two major mechanisms, including formation of DNA adducts [22][23][24] and damage due to ROS generation. 20,25 Ultimately, these processes lead auditory organs to lose functional components by apoptosis or necrosis.…”

Section: Discussionmentioning

confidence: 99%

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

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We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTl-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

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“…30 Additionally, c-Abl has been shown to directly bind, phosphorylate and activate MEKK-1 in response to DNA damage. 31 Further, binding of c-Abl to the p85 subunit of PI3-kinase results in initiation of proapoptotic signals. 32 Recently, caspase-2 has been identified as an initiator caspase for apoptotic signaling induced by DNA damage in some cell lines.…”

Section: Discussionmentioning

confidence: 99%

Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis

2003

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c-Abl protein tyrosine kinase plays an important role in cell cycle control and apoptosis. Furthermore, induction of apoptosis correlates with the activation of c-Abl. Here, we demonstrate the cleavage of c-Abl by caspases during apoptosis. Caspases separate c-Abl into functional domains including a Src-kinase, a fragment containing nuclear import sequences, a fragment with an actin-binding domain and nuclear export sequence. Caspase cleavage increases the kinase activity of c-Abl as demonstrated by in vitro kinase assays as well as by auto-and substrate phosphorylation. Cells in which c-Abl expression was knocked down by RNA interference resisted cisplatin-but not TNFa-induced apoptosis. A similar selective resistance against cisplatin-induced apoptosis was observed when cleavage resistant c-Abl was overexpressed in treated cells. Our data suggest the selective requirement of c-Abl cleavage by caspases for stressinduced, but not for TNFa-induced apoptosis.

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Activation of MEK Kinase 1 by the c-Abl Protein Tyrosine Kinase in Response to DNA Damage

Cited by 83 publications

References 78 publications

Cisplatin Cytotoxicity of Auditory Cells Requires Secretions of Proinflammatory Cytokines via Activation of ERK and NF-κB

Cisplatin Cytotoxicity of Auditory Cells Requires Secretions of Proinflammatory Cytokines via Activation of ERK and NF-κB

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis

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