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Specificity of MAPK signaling towards FLO11 expression is established by crosstalk from cAMP pathway.

ABSTRACT: In budding yeast, elements of a single MAP Kinase cascade are shared to regulate a wide range of functions such as mating, differentiation and osmotic stress. However, cells have programmed to execute correct event in response to a given input signal without cross activating other responses. Studies have observed that magnitude and duration of MAPK activation encodes specificity. Similarly, the differential regulation of Tec1p, a transcriptional activator of invasive growth gene, FLO11 by MAP kinases has been observed to bring specificity in mating and invasive growth signaling. However, the understanding of interactions between the shared components and other signaling pathways related to the phenotypic response in contributing towards specificity remains unclear. We specifically address the crosstalk of cAMP pathway with MAPK pathway in haploid invasive growth and show the contribution and importance of cAMP pathway towards invasive growth irrespective of the activation status of MAPK pathway. Our analysis shows that crosstalk from cAMP pathway in haploids might offer an advantage in terms of amplifying the observed weak signaling through MAPK pathway. Further, we show that such a crosstalk in haploids leads to higher FLO11 expression than diploids. We also demonstrate the positive and negative role of Tpk1 and Tpk3 in haploid invasive growth. Finally, we observe that a cross-inhibition at gene level brought about by cAMP pathway controlled inhibitor, Sfl1, perhaps help in deamplifying the MAPK signal and also in preventing FLO11 expression in the absence of cAMP pathway activation.

SUBMITTER: Vinod PK

PROVIDER: S-EPMC2533523 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Specificity of MAPK signaling towards FLO11 expression is established by crosstalk from cAMP pathway.

Vinod P K PK Venkatesh K V KV

Systems and synthetic biology 20070401 2

In budding yeast, elements of a single MAP Kinase cascade are shared to regulate a wide range of functions such as mating, differentiation and osmotic stress. However, cells have programmed to execute correct event in response to a given input signal without cross activating other responses. Studies have observed that magnitude and duration of MAPK activation encodes specificity. Similarly, the differential regulation of Tec1p, a transcriptional activator of invasive growth gene, FLO11 by MAP ki ...[more]

PMID: 19003439

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Project description:The budding yeast, Saccharomyces cerevisiae, responds to various environmental cues by invoking specific adaptive mechanisms for their survival. Under nitrogen limitation, S. cerevisiae undergoes a dimorphic filamentous transition called pseudohyphae, which helps the cell to forage for nutrients and reach an environment conducive for growth. This transition is governed by a complex network of signaling pathways, namely cAMP-PKA, MAPK and TOR, which controls the transcriptional activation of FLO11, a flocculin gene that encodes a cell wall protein. However, little is known about how these pathways co-ordinate to govern the conversion of nutritional availability into gene expression. Here, we have analyzed an integrative network comprised of cAMP-PKA, MAPK and TOR pathways with respect to the availability of nitrogen source using experimental and steady state modeling approach. Our experiments demonstrate that the steady state expression of FLO11 was bistable over a range of inducing ammonium sulphate concentration based on the preculturing condition. We also show that yeast switched from FLO11 expression to accumulation of trehalose, a STRE response controlled by a transcriptional activator Msn2/4, with decrease in the inducing concentration to complete starvation. Steady state analysis of the integrative network revealed the relationship between the environment, signaling cascades and the expression of FLO11. We demonstrate that the double negative feedback loop in TOR pathway can elicit a bistable response, to differentiate between vegetative growth, filamentous growth and STRE response. Negative feedback on TOR pathway function to restrict the expression of FLO11 under nitrogen starved condition and also with re-addition of nitrogen to starved cells. In general, we show that these global signaling pathways respond with specific sensitivity to regulate the expression of FLO11 under nitrogen limitation. The holistic steady state modeling approach of the integrative network revealed how the global signaling pathways could differentiate between multiple phenotypes.

Project description:BackgroundMucus plays an important role in protecting human airway from external environments. Highly glycosylated mucin proteins are the major components of mucus, responsible for its viscoelastic properties. Excessive mucus is major manifestation of inflammatory respiratory diseases. Epigallocatechin-3-gallate (EGCG) is major component of green tea extract and known to provide numerous functions, such as anti-oxidant effect, anti-tumor effect, anti-diabetic effect and anti-inflammatory effect. But precise mechanisms are still unclear.MethodsUsing NCI-H292 human airway epithelial cells, we measured phorbol 12-myrisate 13-acetate (PMA)-induced MUC5B mRNA expression with the treatment of indicated doses of EGCG. We also measured PMA-induced MUC5B protein secretion with the treatment of indicated doses of EGCG using ELISA technique in NCI-H292 cells. To test the brief signaling pathways, we performed activation study of mitogen-activated protein kinase (MAPK) pathways, which is well-known to signaling the PMA-induced mucin gene over-expression, using Western blot technique in NCI-H292 cells. And then we performed in vivo study using ovalbumin-induced asthmatic mice model and control mice group. In ovalbumin-sensitized asthmatic mice model, EGCG was treated with indicated dose. And then ovalbumin was challenged and we sacrificed the mice. Tissue samples from the mice were stained with PAS (periodic acid-Schiff) for mucin distribution in bronchioles of each group. Immunocytochemical stain was performed using MUC5B specific antibody. MUC5B mRNA and protein level was measured using extracted lung tissues.ResultsPMA-induced MUC5B mRNA and protein level was significantly decreased after treatment of EGCG at all doses in NCI-H292 cells. PMA-induced phosphorylation of p38 MAPK was significantly decreased after treatment of EGCG at all doses in NCI-H292 cells. Results from in vivo studies showed that decreased bronchiolar mucin distribution in the group of pretreated with EGCG in asthmatic mice. MUC5B mRNA and protein levels were significantly decreased in the group of pretreated with EGCG in asthmatic mice.ConclusionsPMA-induced MUC5B mRNA and protein over-expression in both NCI-H292 cells and extracted tissues from asthmatic mice were significantly decreased with the treatment of EGCG. We demonstrated that EGCG downregulates mucin gene expression through the MAPK signaling pathway in asthma.

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Specificity of MAPK signaling towards FLO11 expression is established by crosstalk from cAMP pathway.

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Specificity of MAPK signaling towards FLO11 expression is established by crosstalk from cAMP pathway.

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