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Regulation of serum response factor-driven transcription by MKL2 (megakaryoblastic leukemia 2) in response to BDNF

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Kalita K., Rejmak E., Kaczmarek L., Hetman M.
Acta Neurobiologiae Experimentalis
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2009
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tom 69
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nr 3
SRF-mediated transcription contributes to brain plasticity. However, it is unclear which of the several SRF co-activators participates in transcriptional events underlying the formation and modifi cations of neuronal circuitries. We investigated the role of SRF co-activator, MKL2, in regulation of SRF-driven transcription in neurons. MKL2 expression was observed in newborn cortical or hippocampal neurons in culture as well as in adult rat forebrain. In-situ hybridization showed the presence of MKL2 mRNA in all fi elds of the hippocampus, especially in dentate gyrus. Neither overexpression nor inhibition of MKL2 by shRNA caused apoptotic cell death in neurons. Overexpression of MKL2 in primary cortical neurons enhanced SRF-driven transcription elevated by BDNF stimulation. In addition, inhibition of MKL2 reduced BDNF activation of SRF-driven transcription, on classical SRE promoters. MKL2 is a less potent activator of SRF-mediated transcription than recently studied member from the same family of co-activators MKL1. Interestingly, MKL2 is working as a partial inhibitor of BDNF activated MKL1-dependent transcription in case of promoters with isolated SRF binding sites. These results suggest that MKL2 contributes to BDNF-mediated regulation of SRF-driven gene expression. Particular mode of regulation depends on the presence of a second co-activator MKL1 or the type of SRF binding sites within the regulatory regions of respective genes. FNP Homing - MF EOG to KK, RO1 (NS047341-01) to MH.
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Novel peptidomimetic MMP-9 inhibitors as potential anti-epileptogenic therapeutics

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Khomiak D., Bertran A., Rejmak E., Kaczmarek L.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: Epilepsy is the most widespread neurological disorder (prevalence – 50 million). The recent discoveries suggest that remodelling of the brain extracellular matrix, executed by extracellularly operating proteases, may play a fundamental role in the pathogenesis of epilepsy. One of them, MMP-9 has been particularly linked to epileptogenesis and the functional involvement of MMP-9 in kainic acid and pentylenetetrazole-kindling models of temporal lobe epilepsy demonstrated. AIM(S): Considering the inhibition MMP-9 as a promising therapeutic strategy, MMP-9 Inhibitors of peptidomimetic nature IPR-X, IPR-Y and IPR-Z were developed at Iproteos and initial conjoint testing of these compounds has been performed. METHOD(S): Compounds ability to penetrate blood‑brain barrier was analyzed by PAMPA (Parallel artificial membrane permeability assay. Stability to degradation in liver and cytotoxicity were tested by exposing to rat liver microsomes and by MTT assay, respectively. Selectivity and potency of IPR‑X‑Z were pre‑estimated by fluorescent assay using DQ‑gelatin and recombinant MMP‑9. Finally, the inhibitors’ ability to inhibit cleavage of of MMP-9 substrate – Nectin-3 was tested in primary hippocampal cell culture upon 50 μM glutamate stimulation. RESULTS: PAMPA assay studies yielded in 7.7–13.3% penetration percentage for artificial blood-brain barrier. The values of intrinsic clearance for IPR-X-Z determined by stability in liver microsomes assay ranged from 33 to 46 µL/min/mg protein, indicating moderate degradation. Compounds proved to be non-toxic in MTT cytotoxicity assay, except of IPR-Z at the highest concentration tested (200 µM). IC50 values from DQ‑gelatinase assay were shown to be 4–10 µM. In hippocampal cell cultures compounds inhibited MMP-9 dependent nectin-3 cleavage with 60% of total band intensity remaining on western blot. CONCLUSIONS: The obtained results confirm that IPR‑X, IPR‑Y and IPR‑Z are specific and potent towards MMP-9 and could be further tested in animal models of epileptogenesis. FINANCIAL SUPPORT: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 642881.
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Growth factor and cytokine interactions in myogenesis Part II Expression of IGF binding proteins and protein kinases essential for myogenesis in mouse C2C12 myogenic cells exposed to TNF- alpha and IFN- gamma

100%
Wieteska-Skrzeczynska W., Grzelkowska-Kowalczyk K., Rejmak E.
Polish Journal of Veterinary Sciences
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2011
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tom 14
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nr 3
The aim of the study was to examine potential interactions among IGF-I and proinflammatory cytokines, TNF-α and IFN-γ, in the regulation of local IGF-I bioavailability and cellular proteins mediating myogenic signals. We investigated levels of IGFBP-4, -5, -6, protein kinase Czeta (PKCζ), p38 and extracellular signal-regulated kinase (ERK1/2) in differentiating mouse C2C12 myoblasts. IGF-I significantly stimulated expression of IGFBP-5. TNF-α and IFN-γ attenuated the expression of IGFBP-4 and -6 under basal conditions and in the presence of IGF-I, and inhibited IGF-I-induced IGFBP-5 expression during 5-day myogenesis. TNF-α and IFN-γ markedly attenuated p38 expression in the presence of IGF-I on the 5th day of myogenesis. When combined with IGF-I the cytokines exerted opposite effects on the PKCζ level, i.e. TNF-α caused an increase, whereas IFN-γ reduced the cellular content of this kinase. Exposition of C2C12 myoblasts to IGF-I or cytokines led to the stimulation of ERK1/2 phosphorylation; however, both TNF-α and IFN-γ exerted an inhibitory effect on the activation of ERK1/2 in myoblasts cultured in the presence of IGF-I. We concluded as follows: i) TNF-α and IFN-γ present in the extracellular environment of differentiating C2C12 myoblasts can alter the local bioavailability of IGF-I by inhibiting the expression of IGFBP-4, -5, and -6, ii) the decrease in p38 expression and ERK1/2 phosphorylation in C2C12 myoblasts exposed to cytokines can lead to disturbances in IGF-I-regulated myogenesis.
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Growth factor and cytokine interactions in myogenesis. Part II. Expression of IGF binding proteins and protein kinases essential for myogenesis in mouse C2C12 myogenic cells exposed to TNF-α and IFN-γ

100%
Wieteska-Skrzeczynska W., Grzelkowska-Kowalczyk K., Rejmak E.
Polish Journal of Veterinary Sciences
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2020
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tom 23
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nr 3
5

Activity - dependent cleavage of Nectin-3 is mediated by MMP-9 metalloproteinase

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Rejmak E., Kalita-Bykowska K., Kaczmarek L.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr S
Matrix metalloproteinase-9 regulates pericellular environment through cleavage of protein components of the extracellular matrix as well as cell adhesion molecules. Recently, it has been revealed that MMP-9 plays an important role in the synaptic plasticity. However, only one synaptic target for its enzymatic activity, beta-dystroglycan was identified to date. In this report we show that Nectin-3 the Ca2+- independent immunoglobulin-like cell adhesion molecule, is a potential substrate for MMP-9. We found that NMDA receptor activation resulted in robust ectodomain shedding of Nectin-3 in the hippocampal cultures. The effect was abolished in the presence of NMDA receptor antagonists, APV and MK801. In contrast, pretreatment with either nifedipine or CNQX only partially decreased NMDA-induced Nectin-3 shedding. Using EGTA, the calcium chelator, we showed that NMDA-mediated cleavage of Nectin-3 was calcium dependent. In addition, we observed Nectin-3 cleavage in the presence of calcium ionophore ionomycin. To test if MMP-9 is mediating Nectin-3 shedding we pretreated hippocampal neurons with inhibitor of MMP-9 and found that this tretment completely abolishes Nectin-3 cleavage evoked by wither NMDA or ionomycin. Our results suggest that ecodomain shedding of Nectin-3 is Ca2+-regulated event and MMP-9 can potentially be responsible for these cleavages.
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