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Fus3-triggered Tec1 degradation modulates mating transcriptional output during the pheromone response.

Chou S, Zhao S, Song Y, Liu H, Nie Q - Mol. Syst. Biol. (2008)

Bottom Line: A mathematical model is developed to capture the dynamic formation of the two Ste12 complexes and their interactions with pathway-specific promoters.By model simulations and experimentation, we show that excess Tec1 can impair the mating transcriptional output because of its ability to sequester Ste12, and because of a novel function of Dig2 for the transcription of mating genes.We suggest that Fus3-triggered Tec1 degradation is an important part of the transcriptional induction of mating genes during the pheromone response.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.

ABSTRACT
The yeast transcription factor Ste12 controls both mating and filamentation pathways. Upon pheromone induction, the mitogen-activated protein kinases, Fus3 and Kss1, activate Ste12 by relieving the repression of two functionally redundant Ste12 inhibitors, Dig1 and Dig2. Mating genes are controlled by the Ste12/Dig1/Dig2 complex through Ste12-binding sites, whereas filamentation genes are regulated by the Tec1/Ste12/Dig1 complex through Tec1-binding sites. The two Ste12 complexes are mutually exclusive. During pheromone response, Tec1 is degraded upon phosphorylation by Fus3, preventing cross-activation of the filamentation pathway. Here, we show that a stable Tec1 also impairs the induction of mating genes. A mathematical model is developed to capture the dynamic formation of the two Ste12 complexes and their interactions with pathway-specific promoters. By model simulations and experimentation, we show that excess Tec1 can impair the mating transcriptional output because of its ability to sequester Ste12, and because of a novel function of Dig2 for the transcription of mating genes. We suggest that Fus3-triggered Tec1 degradation is an important part of the transcriptional induction of mating genes during the pheromone response.

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Strategy 1: Ste12/Dig1/Dig2 is more effective than Tec1/Ste12/Dig1 in the transcriptional induction of PREs. Ratio of PRE output for WT cells over PRE output for stable Tec1 strains (R1) versus ratio of PRE output for the tec1 deletion mutant over PRE output for WT cells (R2) at four different times: 30, 60, 90 and 120 min. Each dot represents one case in which the reaction rates are randomly selected. Hundred cases are shown. Red dots represent the cases in which R1>1 and R2>1 at each time. (A) The overall activation rates of Fus3 on Tec1/Ste12/Dig1 and on Ste12/Dig1/Dig2 are assumed to be the same. (B) The overall activation rate of Fus3 on Tec1/Ste12/Dig1 is assumed to be half that of the rate on Ste12/Dig1/Dig2. (C) Experimental measurements of PRE-lacZ levels in WT, dig2, tec1 and dig2 tec1 mutants with 200 nM α-factor.
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f2: Strategy 1: Ste12/Dig1/Dig2 is more effective than Tec1/Ste12/Dig1 in the transcriptional induction of PREs. Ratio of PRE output for WT cells over PRE output for stable Tec1 strains (R1) versus ratio of PRE output for the tec1 deletion mutant over PRE output for WT cells (R2) at four different times: 30, 60, 90 and 120 min. Each dot represents one case in which the reaction rates are randomly selected. Hundred cases are shown. Red dots represent the cases in which R1>1 and R2>1 at each time. (A) The overall activation rates of Fus3 on Tec1/Ste12/Dig1 and on Ste12/Dig1/Dig2 are assumed to be the same. (B) The overall activation rate of Fus3 on Tec1/Ste12/Dig1 is assumed to be half that of the rate on Ste12/Dig1/Dig2. (C) Experimental measurements of PRE-lacZ levels in WT, dig2, tec1 and dig2 tec1 mutants with 200 nM α-factor.

Mentions: When the pheromone-induced activation rate of PRE-lacZ for Tec1/Ste12/Dig1 and Ste12/Dig1/Dig2 is set to be the same, we see that R2 is always smaller than 1 (Figure 2A). For a wide range of reaction rates, the PRE output for stable TEC1T273V cells is always larger than the PRE output of the wild-type cells. In addition, R2 seems to be an inverse function of R1 (Figure 2A). This implies that the ratio of PRE output for TEC1T273V cells over PRE output for tec1 deletion cells hardly changes from case to case in Figure 2A. However, when the pheromone-induced activation rate for the complex Tec1/Ste12/Dig1 is set to be smaller than the activation rate for Ste12/Dig1/Dig2, R1 and R2 are both larger than 1 in our model simulations (Figure 2B). This strategy presumes that the Tec1/Ste12/Dig1 portion of the PRE output is produced less efficiently than the Ste12/Dig1/Dig2 portion of the PRE output. Under this assumption, both R1 and R2 are larger than 1 in most of the cases when other reaction rates randomly vary (red dots in Figure 2B). The overall pattern in Figure 2B is a relatively robust strategy (Supplementary Figures S4, S5 and S11). Therefore, our modeling suggests that the Ste12/Dig1/Dig2 complex may be more effective in the transcriptional activation of PREs than the Tec1/Ste12/Dig1 complex.


Fus3-triggered Tec1 degradation modulates mating transcriptional output during the pheromone response.

Chou S, Zhao S, Song Y, Liu H, Nie Q - Mol. Syst. Biol. (2008)

Strategy 1: Ste12/Dig1/Dig2 is more effective than Tec1/Ste12/Dig1 in the transcriptional induction of PREs. Ratio of PRE output for WT cells over PRE output for stable Tec1 strains (R1) versus ratio of PRE output for the tec1 deletion mutant over PRE output for WT cells (R2) at four different times: 30, 60, 90 and 120 min. Each dot represents one case in which the reaction rates are randomly selected. Hundred cases are shown. Red dots represent the cases in which R1>1 and R2>1 at each time. (A) The overall activation rates of Fus3 on Tec1/Ste12/Dig1 and on Ste12/Dig1/Dig2 are assumed to be the same. (B) The overall activation rate of Fus3 on Tec1/Ste12/Dig1 is assumed to be half that of the rate on Ste12/Dig1/Dig2. (C) Experimental measurements of PRE-lacZ levels in WT, dig2, tec1 and dig2 tec1 mutants with 200 nM α-factor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2538907&req=5

f2: Strategy 1: Ste12/Dig1/Dig2 is more effective than Tec1/Ste12/Dig1 in the transcriptional induction of PREs. Ratio of PRE output for WT cells over PRE output for stable Tec1 strains (R1) versus ratio of PRE output for the tec1 deletion mutant over PRE output for WT cells (R2) at four different times: 30, 60, 90 and 120 min. Each dot represents one case in which the reaction rates are randomly selected. Hundred cases are shown. Red dots represent the cases in which R1>1 and R2>1 at each time. (A) The overall activation rates of Fus3 on Tec1/Ste12/Dig1 and on Ste12/Dig1/Dig2 are assumed to be the same. (B) The overall activation rate of Fus3 on Tec1/Ste12/Dig1 is assumed to be half that of the rate on Ste12/Dig1/Dig2. (C) Experimental measurements of PRE-lacZ levels in WT, dig2, tec1 and dig2 tec1 mutants with 200 nM α-factor.
Mentions: When the pheromone-induced activation rate of PRE-lacZ for Tec1/Ste12/Dig1 and Ste12/Dig1/Dig2 is set to be the same, we see that R2 is always smaller than 1 (Figure 2A). For a wide range of reaction rates, the PRE output for stable TEC1T273V cells is always larger than the PRE output of the wild-type cells. In addition, R2 seems to be an inverse function of R1 (Figure 2A). This implies that the ratio of PRE output for TEC1T273V cells over PRE output for tec1 deletion cells hardly changes from case to case in Figure 2A. However, when the pheromone-induced activation rate for the complex Tec1/Ste12/Dig1 is set to be smaller than the activation rate for Ste12/Dig1/Dig2, R1 and R2 are both larger than 1 in our model simulations (Figure 2B). This strategy presumes that the Tec1/Ste12/Dig1 portion of the PRE output is produced less efficiently than the Ste12/Dig1/Dig2 portion of the PRE output. Under this assumption, both R1 and R2 are larger than 1 in most of the cases when other reaction rates randomly vary (red dots in Figure 2B). The overall pattern in Figure 2B is a relatively robust strategy (Supplementary Figures S4, S5 and S11). Therefore, our modeling suggests that the Ste12/Dig1/Dig2 complex may be more effective in the transcriptional activation of PREs than the Tec1/Ste12/Dig1 complex.

Bottom Line: A mathematical model is developed to capture the dynamic formation of the two Ste12 complexes and their interactions with pathway-specific promoters.By model simulations and experimentation, we show that excess Tec1 can impair the mating transcriptional output because of its ability to sequester Ste12, and because of a novel function of Dig2 for the transcription of mating genes.We suggest that Fus3-triggered Tec1 degradation is an important part of the transcriptional induction of mating genes during the pheromone response.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.

ABSTRACT
The yeast transcription factor Ste12 controls both mating and filamentation pathways. Upon pheromone induction, the mitogen-activated protein kinases, Fus3 and Kss1, activate Ste12 by relieving the repression of two functionally redundant Ste12 inhibitors, Dig1 and Dig2. Mating genes are controlled by the Ste12/Dig1/Dig2 complex through Ste12-binding sites, whereas filamentation genes are regulated by the Tec1/Ste12/Dig1 complex through Tec1-binding sites. The two Ste12 complexes are mutually exclusive. During pheromone response, Tec1 is degraded upon phosphorylation by Fus3, preventing cross-activation of the filamentation pathway. Here, we show that a stable Tec1 also impairs the induction of mating genes. A mathematical model is developed to capture the dynamic formation of the two Ste12 complexes and their interactions with pathway-specific promoters. By model simulations and experimentation, we show that excess Tec1 can impair the mating transcriptional output because of its ability to sequester Ste12, and because of a novel function of Dig2 for the transcription of mating genes. We suggest that Fus3-triggered Tec1 degradation is an important part of the transcriptional induction of mating genes during the pheromone response.

Show MeSH