DNA Topoisomerase I Is a Cofactor for c-Jun in the Regulation of Epidermal Growth Factor Receptor Expression and Cancer Cell Proliferation

Mialon, Antoine; Sankinen, Matti; Söderström, Henrik; Junttila, Teemu T.; Holmström, Tim H.; Koivusalo, Riku; Papageorgiou, Anastassios C.; Johnson, Randall S.; Hietanen, Sakari; Elenius, Klaus; Westermarck, Jukka

doi:10.1128/mcb.25.12.5040-5051.2005

Cited by 48 publications

(41 citation statements)

References 39 publications

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“…We also reason that RRP might be especially beneficial for identification of mechanisms that are regulated by more stochastic and weak interactions. As shown by our previous studies, they may lead to the discovery of an entirely new biological concept (1,5,6). This obviously requires that the identified interaction and its functional relevance are properly verified by subsequent experimentation or, as it is proposed here, filtered by RRP for their functional relevance.…”

Section: Discussionmentioning

confidence: 99%

“…Regardless of these advances, one of the major challenges in protein-protein interaction screens is to dissociate from large number of interactions those that are functionally relevant for a particular biological question. Moreover, even though currently used quantitative methods emphasize the importance of repeatability in weighting the likelihood of an identified interaction to be true (3,4), we cannot exclude even one-time identification of a few peptides of a previously unknown protein, as they may lead to the discovery of an entirely new biological concept, provided the identified interaction and its functional relevance is properly verified by subsequent experimentation (1,(5)(6)(7). Finally, when considering the reliability of the identified putative interaction, the functional classification of candidate interactors to "relevant" versus "nonrelevant" may not be advisable without further supporting data.…”

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confidence: 99%

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Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein–Protein Interaction Data*

Pokharel

Saarela

Szwajda

et al. 2015

Molecular & Cellular Proteomics

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High content protein interaction screens have revolutionized our understanding of protein complex assembly. However, one of the major challenges in translation of high content protein interaction data is identification of those interactions that are functionally relevant for a particular biological question. To address this challenge, we developed a relevance ranking platform (RRP), which consist of modular functional and bioinformatic filters to provide relevance rank among the interactome proteins. We demonstrate the versatility of RRP to enable a systematic prioritization of the most relevant interaction partners from high content data, highlighted by the analysis of cancer relevant protein interactions for oncoproteins Pin1 and PME-1. We validated the importance of selected interactions by demonstration of PTOV1 and CSKN2B as novel regulators of Pin1 target c-Jun phosphorylation and reveal previously unknown interacting proteins that may mediate PME-1 effects via PP2A-inhibition. The RRP framework is modular and can be modified to answer versatile research problems depending on the nature of the biological question under study. Based on comparison of RRP to other existing filtering tools, the presented data indicate that RRP offers added value especially for the analysis of interacting proteins for which there is no sufficient prior knowledge available. Finally, we encourage the use of RRP in combination with either SAINT or CRAPome computational tools for selecting the candidate interactors that fulfill the both important requirements, functional relevance, and high confidence interaction detection. Molecular & Cellular

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein–Protein Interaction Data*

Pokharel

Saarela

Szwajda

et al. 2015

Molecular & Cellular Proteomics

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“…Several reports have shown that activated JNK positively regulates EGFR expression via c-Jun activation (27)(28)(29), and we investigated whether COX-2 regulates JNK activity, resulting in EGFR down-regulation in the tested cancer cells. Overexpressed COX-2 specifically activated JNK compared with control cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies reported that c-Jun transcription factor, a substrate of JNK, positively regulates transcription of the EGFR gene (27)(28)(29). Therefore, we investigated whether JNK is involved in COX-2-induced EGFR down-regulation.…”

Section: Cox-2-activated Jnk Negatively Regulates Egfr Expressionmentioning

confidence: 99%

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

Kim

Park

Pyo

2009

Molecular Cancer Research

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Overexpression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) has been detected in many types of cancer. Although COX-2 and EGFR are closely related to each other, the exact mechanism of COX-2 in tumors has not been well understood. In this study, we investigated the relationship between COX-2 and EGFR in cancer cells. Using two cell lines stably overexpressing COX-2 (HCT-116-COX-2 and H460-COX-2) and a stable line of COX-2 knockdown MOR-P cells, we analyzed patterns of COX-2 and EGFR expression. To observe the effects of COX-2 on EGFR expression and activity, we did comparative analyses after treatment with various drugs (EGF, celecoxib, prostaglandin E 2 , gefitinib, Ro-31-8425, PD98059, and SP600125) in HCT-116-Mock versus HCT-116-COX-2 cells and H460-Mock versus H460-COX-2 cells. Overexpression of COX-2 specifically down-regulated EGFR expression at the level of transcription. COX-2-overexpressing cells have a decreased sensitivity to gefitinib. COX-2 induced activation of extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK) but suppressed Akt activation. JNK inhibition by SP600125, a specific JNK inhibitor, resulted in restoration of EGFR levels in COX-2-overexpressing cells, whereas ERK inhibition by PD98059 did not. Overexpressed COX-2 negatively regulates EGFR expression via JNK activation, leading to gefitinib resistance. COX-2 may also regulate ERK activity independently of EGFR. Therefore, resistance of COX-2-overexpressing cells to gefitinib may be due to decreased expression of EGFR by JNK activation and EGFR-independent elevation of ERK activity by COX-2. The ability of COX-2 to inhibit EGFR expression and gefitinib effects may have significance in clinical cancer therapy.

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“…For example, camptothecin exposure leads to selective reduction of expression of EGFR, HIF-1α and c-Myc [47][48][49], which are genes that strongly promote tumour cell growth and proliferation. Moreover, the bisphenazine XR5944 has been shown to selectively inhibit gene expression from oestrogen receptor binding sites, although not from SP-1 sites, suggesting that topo-targeting compounds that inhibit gene transcription may have unique gene inhibition signatures [50].…”

Section: Discussionmentioning

confidence: 99%

The role of topoisomerases and RNA transcription in the action of the antitumour benzonaphthyridine derivative SN 28049

Bridewell¹,

Porter²,

Finlay³

et al. 2008

Cancer Chemother Pharmacol

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Purpose-SN 28049 (N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide) is a DNA intercalating drug that binds selectively to GC-rich DNA and shows curative activity against the Colon 38 adenocarcinoma in mice. We wished to investigate the roles of topoisomerase (topo) I, topo II and RNA transcription in the action of SN 28049.Methods-We used clonogenic assays to study the cytotoxicity of SN 28049; RNA interference and enzyme assays to examine the role of topo I in SN 28049 action; 3 H uridine incorporation and reporter assays to study its effects on transcription; and RT-PCR to examine its ability to reduce endogenous h-TERT expression. Conclusion-We conclude that SN 28049 has a complex action that may involve poisoning of topo IIα, suppression of topo I and inhibition of gene transcription from promoters with SP-1 sites. These actions may contribute to the promising experimental solid tumour anticancer activity of SN 28049. Results-In

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DNA Topoisomerase I Is a Cofactor for c-Jun in the Regulation of Epidermal Growth Factor Receptor Expression and Cancer Cell Proliferation

Cited by 48 publications

References 39 publications

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein–Protein Interaction Data*

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein–Protein Interaction Data*

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

The role of topoisomerases and RNA transcription in the action of the antitumour benzonaphthyridine derivative SN 28049

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