Ataxia Telangiectasia Mutated Down-regulates Phospho-Extracellular Signal-Regulated Kinase 1/2 via Activation of MKP-1 in Response to Radiation

Nyati, Mukesh K.; Feng, Felix Y.; Maheshwari, Divya; Varambally, Sooryanarayana; Zielske, Steven P.; Ahsan, Aarif; Chun, Patrick Y.; Arora, Vinay A.; Davis, Mary A.; Jung, Mira; Ljungman, Mats; Canman, Christine E.; Chinnaiyan, Arul M.; Lawrence, Theodore S.

doi:10.1158/0008-5472.can-06-1935

Cited by 26 publications

(19 citation statements)

References 26 publications

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“…Furthermore, these findings are consistent with the observation that SKP2 accelerates the abilities of either activated N-RAS or Ha-RAS (both ERK upstream activators) to induce cell transformation and tumor development (45,49). According to recent findings, the Ataxia telangiectasia mutated kinase gene, which plays a crucial role in the cellular response to DNA damage, inhibits ERK activity via increased expression of DUSP1 (50). This observation suggests a new mechanism of the anticancer action of DUSP1 based on the enhancement of DNA repair.…”

Section: Discussionsupporting

confidence: 89%

Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase–Mediated Control of Growth in Human Hepatocellular Carcinoma

et al. 2008

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Sustained activation of extracellular signal-regulated kinase (ERK) has been detected previously in numerous tumors in the absence of RAS-activating mutations. However, the molecular mechanisms responsible for ERK-unrestrained activity independent of RAS mutations remain unknown. Here, we evaluated the effects of the functional interactions of ERK proteins with dual-specificity phosphatase 1 (DUSP1), a specific inhibitor of ERK, and S-phase kinase-associated protein 2 (SKP2)/ CDC28 protein kinase 1b (CKS1) ubiquitin ligase complex in human hepatocellular carcinoma (HCC). Levels of DUSP1, as assessed by real-time reverse transcription-PCR and Western blot analysis, were significantly higher in tumors with better prognosis (as defined by the length of patients' survival) when compared with both normal and nontumorous surrounding livers, whereas DUSP1 protein expression sharply declined in all HCC with poorer prognosis. In the latter HCC subtype, DUSP1 inactivation was due to either ERK/SKP2/CKS1-dependent ubiquitination or promoter hypermethylation associated with loss of heterozygosity at the DUSP1 locus. Noticeably, expression levels of DUSP1 inversely correlated with those of activated ERK, as well as with proliferation index and microvessel density, and directly with apoptosis and survival rate. Subsequent functional studies revealed that DUSP1 reactivation led to suppression of ERK, CKS1, and SKP2 activity, inhibition of proliferation and induction of apoptosis in human hepatoma cell lines. Taken together, the present data indicate that ERK achieves unrestrained activity during HCC progression by triggering ubiquitin-mediated proteolysis of its specific inhibitor DUSP1. Thus, DUSP1 may represent a valuable prognostic marker and ERK, CKS1, or SKP2 potential therapeutic targets for human HCC.

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Section: Discussionsupporting

confidence: 89%

Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase–Mediated Control of Growth in Human Hepatocellular Carcinoma

et al. 2008

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“…The ERK pathway has long been considered a major factor in producing radioresistance possibly through its ability to up-regulate the transcription of DNA repair genes when activated (31). Moreover, two recent papers illustrate direct relationships between the ERK pathway and the ATM kinase (32,33). In our experiments, however, gefitinib did not seem to affect the radiationinduced activation of ATM (Fig.…”

Section: Discussionmentioning

confidence: 44%

Gefitinib Radiosensitizes Non–Small Cell Lung Cancer Cells by Suppressing Cellular DNA Repair Capacity

Tanaka

Munshi

Brooks

et al. 2008

Clinical Cancer Research

116

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Purpose: Overexpression of the epidermal growth factor receptor (EGFR) promotes unregulated growth, inhibits apoptosis, and likely contributes to clinical radiation resistance of non^small cell lung cancer (NSCLC). Molecular blockade of EGFR signaling is an attractive therapeutic strategy for enhancing the cytotoxic effects of radiotherapy that is currently under investigation in preclinical and clinical studies. In the present study, we have investigated the mechanism by which gefitinib, a selective EGFR tyrosine kinase inhibitor, restores the radiosensitivity of NSCLC cells. Experimental Design: Two NSCLC cell lines, A549 and H1299, were treated with 1 Amol/L gefitinib for 24 h before irradiation and then tested for clonogenic survival and capacity for repairing DNA double strand breaks (DSB). Four different repair assays were used: host cell reactivation, detection of g-H2AX and pNBS1 repair foci using immunofluorescence microscopy, the neutral comet assay, and pulsed-field gel electrophoresis. Results: In clonogenic survival experiments, gefitinib had significant radiosensitizing effects on both cell lines. Results from all four DNA damage repair analyses in cultured A549 and H1299 cells showed that gefitinib had a strong inhibitory effect on the repair of DSBs after ionizing radiation.The presence of DSBs was especially prolonged during the first 2 h of repair compared with controls. Immunoblot analysis of selected repair proteins indicated that pNBS1 activation was prolonged by gefitinib correlating with its effect on pNBS1-labeled repair foci. Conclusions: Overall, we conclude that gefitinib enhances the radioresponse of NSCLC cells by suppressing cellular DNA repair capacity, thereby prolonging the presence of radiation-induced DSBs.

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“…More recently, both normal human skin fibroblasts and A431 cells up-regulated ataxia telangiectasia-mutated kinase activity in response to radiation, which led to dephosphorylation of ERK1/2 in an MKP-1-dependant manner. The results of ERK1/2 dephosphorylation by MKP-1 were reprised in a xenograft model using A431 cells and irradiated nude mice (Nyati et al, 2006). Short-wavelength ultraviolet light (UVC) up-regulates ERK2 and JNK1 activities followed by an increase in MKP-1 protein levels, leading to down-regulation of JNK1 activity in HeLa cells (Liu et al, 1995).…”

Section: (Z)-1-[n-(2-aminoethyl)-n-(2-ammonioethyl) Amino]diazen-1-mentioning

confidence: 99%

Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer

Boutros

Chevet²,

Metrakos³

2008

Pharmacol Rev

510

448

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Ataxia Telangiectasia Mutated Down-regulates Phospho-Extracellular Signal-Regulated Kinase 1/2 via Activation of MKP-1 in Response to Radiation

Cited by 26 publications

References 26 publications

Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase–Mediated Control of Growth in Human Hepatocellular Carcinoma

Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase–Mediated Control of Growth in Human Hepatocellular Carcinoma

Gefitinib Radiosensitizes Non–Small Cell Lung Cancer Cells by Suppressing Cellular DNA Repair Capacity

Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer

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