Publications by authors named "Hanne Kildalsen"

5 Publications

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Phosphorylation of steroid receptor coactivator-3 (SRC-3) at serine 857 is regulated by the p38-MK2 axis and affects NF-κB-mediated transcription.

Sci Rep 2020 07 9;10(1):11388. Epub 2020 Jul 9.

Department of Pharmacy, UiT The Arctic University of Norway, 9037, Tromsø, Norway.

Steroid receptor coactivator-3 (SRC-3) regulates the activity of both nuclear hormone receptors and a number of key transcription factors. It is implicated in the regulation of cell proliferation, inflammation and in the progression of several common cancers including breast, colorectal and lung tumors. Phosphorylation is an important regulatory event controlling the activities of SRC-3. Serine 857 is the most studied phospho-acceptor site, and its modification has been reported to be important for SRC-3-dependent tumor progression. In this study, we show that the stress-responsive p38-MK2 signaling pathway controls the phosphorylation of SRC-3 at S857 in a wide range of human cancer cells. Activation of the p38-MK2 pathway results in the nuclear translocation of SRC-3, where it contributes to the transactivation of NF-kB and thus regulation of IL-6 transcription. The identification of the p38-MK2 signaling axis as a key regulator of SRC-3 phosphorylation and activity opens up new possibilities for the development and testing of novel therapeutic strategies to control both proliferative and metastatic tumor growth.
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http://dx.doi.org/10.1038/s41598-020-68219-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347898PMC
July 2020

Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors.

J Med Chem 2018 09 23;61(17):7560-7572. Epub 2018 Aug 23.

The Norwegian Structural Biology Centre, Department of Chemistry , UiT The Arctic University of Norway , N-9037 Tromsø , Norway.

DYRK1A is one of five members of the dual-specificity tyrosine (Y) phosphorylation-regulated kinase (DYRK) family. The DYRK1A gene is located in the Down syndrome critical region and regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells during early development. This has focused research on its role in neuronal degenerative diseases, including Alzheimer's and Down syndrome. Recent studies have also shown a possible role of DYRK1A in diabetes. Here we report a variety of scaffolds not generally known for DYRK1A inhibition, demonstrating their effects in in vitro assays and also in cell cultures. These inhibitors effectively block the tau phosphorylation that is a hallmark of Alzheimer's disease. The crystal structures of these inhibitors support the design of optimized and novel therapeutics.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01847DOI Listing
September 2018

Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2.

Sci Rep 2017 03 2;7:43471. Epub 2017 Mar 2.

Department of Pharmacy UiT The Arctic University of Norway, N-9037 Tromsø, Norway.

The atypical MAP kinases ERK3 and ERK4 are activated by phosphorylation of a serine residue lying within the activation loop signature sequence S-E-G. However, the regulation of ERK3 and ERK4 phosphorylation and activity is poorly understood. Here we report that the inducible nuclear dual-specificity MAP kinase phosphatase (MKP) DUSP2, a known regulator of the ERK and p38 MAPKs, is unique amongst the MKP family in being able to bind to both ERK3 and ERK4. This interaction is mediated by a conserved common docking (CD) domain within the carboxyl-terminal domains of ERK3 and ERK4 and the conserved kinase interaction motif (KIM) located within the non-catalytic amino terminus of DUSP2. This interaction is direct and results in the dephosphorylation of ERK3 and ERK4 and the stabilization of DUSP2. In the case of ERK4 its ability to stabilize DUSP2 requires its kinase activity. Finally, we demonstrate that expression of DUSP2 inhibits ERK3 and ERK4-mediated activation of its downstream substrate MK5. We conclude that the activity of DUSP2 is not restricted to the classical MAPK pathways and that DUSP2 can also regulate the atypical ERK3/4-MK5 signalling pathway in mammalian cells.
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http://dx.doi.org/10.1038/srep43471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333157PMC
March 2017

S100A4 expression in xenograft tumors of human carcinoma cell lines is induced by the tumor microenvironment.

Am J Pathol 2011 May;178(5):2389-96

Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.

Increased expression of the invasion- and metastasis-associated protein S100A4 is found in many types of cancer, but the regulation of S100A4 expression is poorly understood. The microenvironment surrounding tumors has a significant effect on tumor progression, and in the present study, we investigated the role of the microenvironment in the expression of S100A4. Tumors of three different human carcinoma cell lines were established in the tongue or skin of mice, and S100A4 expression was assessed by quantitative RT-PCR, Western blotting, and immunohistochemical analysis in tumors and stromal tissue and in cancer cells grown in vitro. Tongue tumors of the oral squamous cell carcinoma cell line HSC-4 showed a pronounced increase in S100A4 expression during tumor growth, whereas only a minor increase was detected in skin tumors of the same cell line. The S100A4 expression correlated with the methylation status of cytosine-guanine sites in the first intron of the gene. For all cell lines, S100A4 expression in the tumor stroma was related to the presence of inflammatory cells rather than to the level of S100A4 in the tumor cells.
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http://dx.doi.org/10.1016/j.ajpath.2011.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081199PMC
May 2011

Collagen I regulates matrix metalloproteinase-2 activation in osteosarcoma cells independent of S100A4.

FEBS J 2009 Sep 13;276(18):5275-86. Epub 2009 Aug 13.

Department of Pharmacy, University of Tromsø, Norway.

This work investigates the effect of cell-collagen I interactions on the synthesis and activation of MMP-2, as well as synthesis of MT1-MMP and TIMP-1, by using an in vitro model with 3D fibrillar and 2D monomeric collagen. In order to reveal whether the metastasis-associated protein S100A4 can influence the cell's response to the two forms of collagen, osteosarcoma cell lines with high and low endogenous levels of S100A4 were used. Attachment of osteosarcoma cells to 3D fibrillar and 2D monomeric collagen resulted in opposite effects on MMP-2 activation. Attachment to 3D fibrillar collagen decreased activation of proMMP-2, with a corresponding reduction in MT1-MMP. By contrast, attachment to monomeric collagen increased the amount of fully active MMP-2. This was caused by a reduction in TIMP-1 levels when cells were attached to monomeric 2D collagen. The effect of collagen on proMMP-2 activation was independent of endogenous S100A4 levels, whereas synthesis of TIMP-1 was dependent on S100A4. When cells were attached to monomeric collagen, cells with a high level of S100A4 showed a greater reduction in the synthesis of TIMP-1 than did those with a low level of S100A4. Taken together, this study shows that synthesis and activation of MMP-2 is affected by interactions between osteosarcoma cells and collagen I in both fibrillar and monomeric form.
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http://dx.doi.org/10.1111/j.1742-4658.2009.07223.xDOI Listing
September 2009