Embryonic Lethal Abnormal Vision-like HuR-dependent mRNA Stability Regulates Post-transcriptional Expression of Cyclin-dependent Kinase Inhibitor p27Kip1

Ziegeler, Gudrun; Ming, Jie; Koseki, Jana C.; Sevinc, S.; Chen, Ting; Ergün, Süleyman; Qin, Xuebin; Aktas, Bertal H.

doi:10.1074/jbc.m110.113365

Cited by 26 publications

(24 citation statements)

References 32 publications

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“…Aside from a transcription factor activation-mediated mechanism acting directly on the p21 and p27 promoters, an alternative mode of action could be through mRNA stability. MKK3 signaling is associated with increased mRNA stability of transcripts with adenosine/uridine-rich elements in the 3 0 untranslated region (3 0 -UTR) in breast cancer cells (48), and p21 and p27 expression are known to be regulated through RNA stabilization mechanisms (49)(50)(51). It remains unclear precisely how MKK3 activity can direct p21 and p27 expression leading to cell-cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

MAPK Kinase 3 Is a Tumor Suppressor with Reduced Copy Number in Breast Cancer

et al. 2014

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Cancers are initiated as a result of changes that occur in the genome. Identification of gains and losses in the structure and expression of tumor-suppressor genes and oncogenes lies at the root of the understanding of cancer cell biology. Here, we show that the mitogen-activated protein kinase (MAPK) MKK3 suppresses the growth of breast cancer, in which it varies in copy number. A pervasive loss of MKK3 gene copy number in patients with breast cancer is associated with an impairment of MKK3 expression and protein level in malignant tissues. To assess the functional role of MKK3 in breast cancer, we showed in an animal model that MKK3 activity is required for suppression of tumor growth. Active MKK3 enhanced expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p27 Kip1 , leading to increased cell-cycle arrest in G 1 phase of the cell cycle. Our results reveal the functional significance of MKK3 as a tumor suppressor and improve understanding of the dynamic role of the MAPK pathway in tumor progression. Cancer Res; 74(1); 162-72. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

MAPK Kinase 3 Is a Tumor Suppressor with Reduced Copy Number in Breast Cancer

et al. 2014

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“…The details of assay development and validation have been described elsewhere. 6,45 The non-symmetrical N,N’ -diarylureas were also evaluated for growth inhibition in the KLN-205, CRL-2351, and human CRL-2813 melanoma cells using the sulforhoadamine B (SRB) assay (Table 1). 11 These cell lines were chosen because they represent prevalent cancers and in preliminary studies they were used by us to validate the TC assay.…”

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confidence: 99%

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

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Chen

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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Symmetrical N,N’-diarylureas: 1,3-bis(3,4-dichlorophenyl)-, 1,3-bis[4-chloro-3(trifluoromethyl) phenyl]- and 1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea, were identified as potent activators of the eIF2α kinase heme regulated inhibitor. They reduce the abundance of the eIF2·GTP·tRNAiMet ternary complex and inhibit cancer cell proliferation. An optimization process was undertaken to improve their solubility while preserving their biological activity. Non-symmetrical hybrid ureas were generated by combining one of the hydrophobic phenyl moieties present in the symmetrical ureas with the polar 3-hydroxy-tolyl moiety. O-alkylation of the later added potentially solubilizing charge bearing groups. The new non-symmetrical N,N’-diarylureas were characterized by ternary complex reporter gene and cell proliferation assays, demonstrating good bioactivities. A representative sample of these compounds potently induced phosphorylation of eIF2α and expression of CHOP at the protein and mRNA levels. These inhibitors of translation initiation may become leads for the development of potent, non-toxic, and target specific anti-cancer agents.

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“…[16-17] Briefly, this assay takes advantage of the fact that phosphorylation of eIF2α reduces the overall rate of translation initiation while paradoxically increasing the translation of a subset of mRNAs containing multiple upstream open reading frames (ORF) in their 5’untranslated regions (5’UTR). These include mRNA coding for activating transcription factor 4 (ATF-4).…”

Section: Resultsmentioning

confidence: 99%

Dual Activators of Protein Kinase R (PKR) and Protein Kinase R‐Like Kinase (PERK) Identify Common and Divergent Catalytic Targets

et al. 2013

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Chemical genetics has evolved into a powerful tool for studying gene function in normal- and patho-biology. PKR and PERK, two eukaryotic translation initiation factor 2 alpha (eIF2α) kinases, play critical roles in maintenance of cellular hemostasis, metabolic stability, and anti-viral defenses. Both kinases interact with and phosphorylate additional substrates including tumor suppressor p53 and nuclear protein 90. Loss of function of both kinases has been studied by reverse genetics and recently identified inhibitors. In contrast, activating probes for studying the role of catalytic activity of these kinases are not available. We identified a 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dihydroxy-4H-chromen-4-one (DHBDC) as specific dual activator of PKR and PERK by screening a chemical library of 20,000 small molecules in a dual luciferase surrogate eIF2α phosphorylation assay. We present here extensive biological characterization and preliminary structure-activity relationship of DHBDC, which phosphorylate eIF2α by activating PKR and PERK but no other eIF2α kinases. These agents also activate downstream effectors of eIF2α phosphorylation; inducing CHOP and suppressing cyclin D1 expression and inhibiting cancer cell proliferation, all in a manner dependent on PKR and PERK. Consistent with the role of eIF2α phosphorylation in viral infection, DHBDC inhibits proliferation of human hepatitis C virus. Finally, DHBDC induces phosphorylation of Ikβα, and activates NF-κB pathway. Surprisingly, activation of NF-κB pathway is dependent on PERK but independent of PKR activity. These data indicate that DHBDC is an invaluable probe for elucidating the role of PKR and PERK in normal- and patho-biology.

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Embryonic Lethal Abnormal Vision-like HuR-dependent mRNA Stability Regulates Post-transcriptional Expression of Cyclin-dependent Kinase Inhibitor p27Kip1

Cited by 26 publications

References 32 publications

MAPK Kinase 3 Is a Tumor Suppressor with Reduced Copy Number in Breast Cancer

MAPK Kinase 3 Is a Tumor Suppressor with Reduced Copy Number in Breast Cancer

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

Dual Activators of Protein Kinase R (PKR) and Protein Kinase R‐Like Kinase (PERK) Identify Common and Divergent Catalytic Targets

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