Institute of Fundamental Technological Research
Polish Academy of Sciences

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Gerhard Müller-Newen

RWTH Aachen University (DE)

Recent publications
1.  Topolewski P., Zakrzewska K.E., Walczak J., Nienałtowski K., Müller-Newen G., Singh A., Komorowski M., Phenotypic variability, not noise, accounts for most of the cell-to-cell heterogeneity in IFN-γ and oncostatin M signaling responses, Science Signaling, ISSN: 1945-0877, DOI: 10.1126/scisignal.abd9303, Vol.15, No.721, pp.eabd9303-1-16, 2022

Abstract:
Cellular signaling responses show substantial cell-to-cell heterogeneity, which is often ascribed to the inherent randomness of biochemical reactions, termed molecular noise, wherein high noise implies low signaling fidelity. Alternatively, heterogeneity could arise from differences in molecular content between cells, termed molecular phenotypic variability, which does not necessarily imply imprecise signaling. The contribution of these two processes to signaling heterogeneity is unclear. Here, we fused fibroblasts to produce binuclear syncytia to distinguish noise from phenotypic variability in the analysis of cytokine signaling. We reasoned that the responses of the two nuclei within one syncytium could approximate the signaling outcomes of two cells with the same molecular content, thereby disclosing noise contribution, whereas comparison of different syncytia should reveal contribution of phenotypic variability. We found that ~90% of the variance in the primary response (which was the abundance of phosphorylated, nuclear STAT) to stimulation with the cytokines interferon-γ and oncostatin M resulted from differences in the molecular content of individual cells. Thus, our data reveal that cytokine signaling in the system used here operates in a reproducible, high-fidelity manner.

Affiliations:
Topolewski P. - IPPT PAN
Zakrzewska K.E. - IPPT PAN
Walczak J. - IPPT PAN
Nienałtowski K. - IPPT PAN
Müller-Newen G. - RWTH Aachen University (DE)
Singh A. - University of Delaware (US)
Komorowski M. - IPPT PAN
2.  Martincuks A., Andryka K., Küster A., Schmitz-Van de Leur H., Komorowski M., Müller-Newen G., Nuclear translocation of STAT3 and NF-κB are independent of each other but NF-κB supports expression and activation of STAT3, Cellular Signalling, ISSN: 0898-6568, DOI: 10.1016/j.cellsig.2017.01.006, Vol.32, pp.36-47, 2017

Abstract:
NF-κB and STAT3 are essential transcription factors in immunity and act at the interface of the transition from chronic inflammation to cancer. Different functional crosstalks between NF-κB and STAT3 have been recently described arguing for a direct interaction of both proteins. During a systematic analysis of NF-κB/STAT3 crosstalk we observed that appearance of the subcellular distribution of NF-κB and STAT3 in immunofluorescence heavily depends on the fixation procedure. Therefore, we established an optimized fixation protocol for the reliable simultaneous analysis of the subcellular distributions of both transcription factors. Using this protocol we found that cytokine-induced nuclear accumulation of NF-κB or STAT3 did not alter the subcellular distribution of the other transcription factor. Both knockout and overexpression of STAT3 does not have any major effect on canonical TNFα-NF-κB signalling in MEF or HeLa cells. Similarly, knockout of p65 did not alter nuclear accumulation of STAT3 in response to IL-6. However, p65 expression correlates with elevated total cellular levels of STAT3 and STAT1 and supports activation of these transcription factors. Our findings in MEF cells argue against a direct physical interaction of free cellular NF-κB and STAT3 but point to more intricate functional interactions.

Keywords:
STAT3, NF-κB, Signal transduction, Nuclear translocation, Crosstalk

Affiliations:
Martincuks A. - RWTH Aachen University (DE)
Andryka K. - other affiliation
Küster A. - RWTH Aachen University (DE)
Schmitz-Van de Leur H. - RWTH Aachen University (DE)
Komorowski M. - IPPT PAN
Müller-Newen G. - RWTH Aachen University (DE)

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