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A systems approach identifies co-signaling molecules of early growth response 1 transcription factor in immobilization stress.

Papanikolaou NA, Tillinger A, Liu X, Papavassiliou AG, Sabban EL - BMC Syst Biol (2014)

Bottom Line: The transcription factor Egr1 plays a central role in acute and repeated stress, however the complexity of the response suggests that other transcription factor pathways might be playing equally important roles during acute and repeated stress.Therefore, we sought to discover such factors by applying a systems approach.Our results suggest possible involvement of Stat3 and Prlh1/Chgb up-regulation in the transition from short to repeated stress activation.

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Affiliation: Laboratory of Biological Chemistry, Department of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Hellas (Greece). papanikn@med.auth.gr.

ABSTRACT

Background: Adaptation to stress is critical for survival. The adrenal medulla, the major source of epinephrine, plays an important role in the development of the hyperadenergic state and increased risk for stress associated disorders, such as hypertension and myocardial infarction. The transcription factor Egr1 plays a central role in acute and repeated stress, however the complexity of the response suggests that other transcription factor pathways might be playing equally important roles during acute and repeated stress. Therefore, we sought to discover such factors by applying a systems approach.

Results: Using microarrays and network analysis we show here for the first time that the transcription factor signal transducer and activator of transcription 3 (Stat3) gene is activated in acute stress whereas the prolactin releasing hormone (Prlh11) and chromogranin B (Chgb) genes are induced in repeated immobilization stress and that along with Egr1 may be critical mediators of the stress response.

Conclusions: Our results suggest possible involvement of Stat3 and Prlh1/Chgb up-regulation in the transition from short to repeated stress activation.

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mRNA levels of Stat3 (panel A) and Prlh1 (panel B) in control, 1× or 6× IMO stress samples, were detected with real time PCR. Fold induction is on the x axis and category on the y axis. Statistical significance was determined as described in Methods. **p ≤ 0.01 compared to control.
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Figure 4: mRNA levels of Stat3 (panel A) and Prlh1 (panel B) in control, 1× or 6× IMO stress samples, were detected with real time PCR. Fold induction is on the x axis and category on the y axis. Statistical significance was determined as described in Methods. **p ≤ 0.01 compared to control.

Mentions: In order to confirm our findings, we tested independent samples of 1× and 6× Egr1 network neighbors for expression changes with qRT-PCR or immunoblots (Tables 4 and 5). Several of these changes were further verified in independent IMO stress samples at the mRNA level by qRT-PCR or at the protein level by western blot analysis or immunocytochemistry (Table 4). These findings confirm for the first time that Stat 3 expression (Figure 4, panel A) is significantly up-regulated with 1× IMO. Expression of Prlh1 (and of Chgb) is up-regulated in both 1× and in 6× (Figure 4, panel B). Strikingly, we observed for the first time down regulation of gene PIAS3 (Inhibitor of Stat 3, Table 4, bottom) implicating Stat3 signaling in acute IMO stress activation. PIAS3 is a small E3-type small ubiquitin-like modifier (SUMO) ligase that plays a critical role in regulating the Stat3 signaling pathway by inhibiting Stat3-DNA binding [28],[29]. The Egr1 neighbors Prlh11 (and Chgb) are significantly represented in changes in the 6× IMO samples, suggesting that they might have important functions in long-term stress signaling (Figure 4, panel B).


A systems approach identifies co-signaling molecules of early growth response 1 transcription factor in immobilization stress.

Papanikolaou NA, Tillinger A, Liu X, Papavassiliou AG, Sabban EL - BMC Syst Biol (2014)

mRNA levels of Stat3 (panel A) and Prlh1 (panel B) in control, 1× or 6× IMO stress samples, were detected with real time PCR. Fold induction is on the x axis and category on the y axis. Statistical significance was determined as described in Methods. **p ≤ 0.01 compared to control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363937&req=5

Figure 4: mRNA levels of Stat3 (panel A) and Prlh1 (panel B) in control, 1× or 6× IMO stress samples, were detected with real time PCR. Fold induction is on the x axis and category on the y axis. Statistical significance was determined as described in Methods. **p ≤ 0.01 compared to control.
Mentions: In order to confirm our findings, we tested independent samples of 1× and 6× Egr1 network neighbors for expression changes with qRT-PCR or immunoblots (Tables 4 and 5). Several of these changes were further verified in independent IMO stress samples at the mRNA level by qRT-PCR or at the protein level by western blot analysis or immunocytochemistry (Table 4). These findings confirm for the first time that Stat 3 expression (Figure 4, panel A) is significantly up-regulated with 1× IMO. Expression of Prlh1 (and of Chgb) is up-regulated in both 1× and in 6× (Figure 4, panel B). Strikingly, we observed for the first time down regulation of gene PIAS3 (Inhibitor of Stat 3, Table 4, bottom) implicating Stat3 signaling in acute IMO stress activation. PIAS3 is a small E3-type small ubiquitin-like modifier (SUMO) ligase that plays a critical role in regulating the Stat3 signaling pathway by inhibiting Stat3-DNA binding [28],[29]. The Egr1 neighbors Prlh11 (and Chgb) are significantly represented in changes in the 6× IMO samples, suggesting that they might have important functions in long-term stress signaling (Figure 4, panel B).

Bottom Line: The transcription factor Egr1 plays a central role in acute and repeated stress, however the complexity of the response suggests that other transcription factor pathways might be playing equally important roles during acute and repeated stress.Therefore, we sought to discover such factors by applying a systems approach.Our results suggest possible involvement of Stat3 and Prlh1/Chgb up-regulation in the transition from short to repeated stress activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Biological Chemistry, Department of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Hellas (Greece). papanikn@med.auth.gr.

ABSTRACT

Background: Adaptation to stress is critical for survival. The adrenal medulla, the major source of epinephrine, plays an important role in the development of the hyperadenergic state and increased risk for stress associated disorders, such as hypertension and myocardial infarction. The transcription factor Egr1 plays a central role in acute and repeated stress, however the complexity of the response suggests that other transcription factor pathways might be playing equally important roles during acute and repeated stress. Therefore, we sought to discover such factors by applying a systems approach.

Results: Using microarrays and network analysis we show here for the first time that the transcription factor signal transducer and activator of transcription 3 (Stat3) gene is activated in acute stress whereas the prolactin releasing hormone (Prlh11) and chromogranin B (Chgb) genes are induced in repeated immobilization stress and that along with Egr1 may be critical mediators of the stress response.

Conclusions: Our results suggest possible involvement of Stat3 and Prlh1/Chgb up-regulation in the transition from short to repeated stress activation.

Show MeSH
Related in: MedlinePlus