Burst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.

Bone Morphogenetic Proteins (BMPs) are important growth factors that regulate many cellular processes. During embryogenesis they act as morphogens and play a critical role during organ development. They influence cell fates via concentration-gradients in the embryos where cells transduce this extrac...

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Autores principales:	Daniela Schul, Alexandra Schmitt, Janine Regneri, Manfred Schartl, Toni Ulrich Wagner
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/66308907791c45efa1632f6755026412
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spelling	oai:doaj.org-article:66308907791c45efa1632f67550264122021-11-18T07:51:15ZBurst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.1932-620310.1371/journal.pone.0059442https://doaj.org/article/66308907791c45efa1632f67550264122013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23560048/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Bone Morphogenetic Proteins (BMPs) are important growth factors that regulate many cellular processes. During embryogenesis they act as morphogens and play a critical role during organ development. They influence cell fates via concentration-gradients in the embryos where cells transduce this extracellular information into gene expression profiles and cell fate decisions. How receiving cells decode and quantify BMP2/4 signals is hardly understood. There is little data on the quantitative relationships between signal input, transducing molecules, their states and location, and ultimately their ability to integrate graded systemic inputs and generate qualitative responses. Understanding this signaling network on a quantitative level should be considered a prerequisite for efficient pathway modulation, as the BMP pathway is a prime target for therapeutic invention. Hence, we quantified the spatial distribution of the main signal transducer of the BMP2/4 pathway in response to different types and levels of stimuli in c2c12 cells. We found that the subcellular localization of Smad1 is independent of ligand concentration. In contrast, Smad1 phosphorylation levels relate proportionally to BMP2 ligand concentrations and they are entirely located in the nucleus. Interestingly, we found that BMP2 stimulates target gene expression in non-linear, wave-like forms. Amplitudes showed a clear concentration-dependency, for sustained and transient stimulation. We found that even burst-stimulation triggers gene-expression wave-like modulations that are detectable for at least 30 h. Finally, we show here that target gene expression oscillations depend on receptor kinase activity, as the kinase drives further expression pulses without receptor reactivation and the target gene expression breaks off after inhibitor treatment in c2c12 cells.Daniela SchulAlexandra SchmittJanine RegneriManfred SchartlToni Ulrich WagnerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e59442 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Daniela Schul Alexandra Schmitt Janine Regneri Manfred Schartl Toni Ulrich Wagner Burst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.
description	Bone Morphogenetic Proteins (BMPs) are important growth factors that regulate many cellular processes. During embryogenesis they act as morphogens and play a critical role during organ development. They influence cell fates via concentration-gradients in the embryos where cells transduce this extracellular information into gene expression profiles and cell fate decisions. How receiving cells decode and quantify BMP2/4 signals is hardly understood. There is little data on the quantitative relationships between signal input, transducing molecules, their states and location, and ultimately their ability to integrate graded systemic inputs and generate qualitative responses. Understanding this signaling network on a quantitative level should be considered a prerequisite for efficient pathway modulation, as the BMP pathway is a prime target for therapeutic invention. Hence, we quantified the spatial distribution of the main signal transducer of the BMP2/4 pathway in response to different types and levels of stimuli in c2c12 cells. We found that the subcellular localization of Smad1 is independent of ligand concentration. In contrast, Smad1 phosphorylation levels relate proportionally to BMP2 ligand concentrations and they are entirely located in the nucleus. Interestingly, we found that BMP2 stimulates target gene expression in non-linear, wave-like forms. Amplitudes showed a clear concentration-dependency, for sustained and transient stimulation. We found that even burst-stimulation triggers gene-expression wave-like modulations that are detectable for at least 30 h. Finally, we show here that target gene expression oscillations depend on receptor kinase activity, as the kinase drives further expression pulses without receptor reactivation and the target gene expression breaks off after inhibitor treatment in c2c12 cells.
format	article
author	Daniela Schul Alexandra Schmitt Janine Regneri Manfred Schartl Toni Ulrich Wagner
author_facet	Daniela Schul Alexandra Schmitt Janine Regneri Manfred Schartl Toni Ulrich Wagner
author_sort	Daniela Schul
title	Burst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.
title_short	Burst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.
title_full	Burst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.
title_fullStr	Burst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.
title_full_unstemmed	Burst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.
title_sort	burst bmp triggered receptor kinase activity drives smad1 mediated long-term target gene oscillation in c2c12 cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/66308907791c45efa1632f6755026412
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Burst BMP triggered receptor kinase activity drives Smad1 mediated long-term target gene oscillation in C2C12 cells.

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