Complex regulation of Hsf1-Skn7 activities by the catalytic subunits of PKA in Saccharomyces cerevisiae experimental and computational evidences

Background: The cAMP-dependent protein kinase regulatory network (PKA-RN) regulates metabolism, memory, learning, development, and response to stress. Previous models of this network considered the catalytic subunits (CS) as a single entity, overlooking their functional individualities. Furthermore, PKA-RN dynamics are often measured through cAMP levels in nutrient-depleted cells shortly after being fed with glucose, dismissing downstream physiological processes. Results: Here we show that temperature stress, along with deletion of PKA-RN genes, significantly affected HSE-dependent gene expression and the dynamics of the PKA-RN in cells growing in exponential phase. Our genetic analysis revealed complex regulatory interactions between the CS that influenced the inhibition of Hsf1/Skn7 transcription factors. Accordingly, we found new roles in growth control and stress response for Hsf1/Skn7 when PKA activity was low (cdc25Δ cells). Experimental results were used to propose an interaction scheme for the PKA-RN and to build an extension of a classic synchronous discrete modeling framework. Our computational model reproduced the experimental data and predicted complex interactions between the CS and the existence of a repressor of Hsf1/Skn7 that is activated by the CS. Additional genetic analysis identified Ssa1 and Ssa2 chaperones as such repressors. Further modeling of the new data foresaw a third repressor of Hsf1/Skn7, active only in theabsence of Tpk2. By averaging the network state over all its attractors, a good quantitative agreement between computational and experimental results was obtained, as the averages reflected more accurately the population measurements. Conclusions: The assumption of PKA being one molecular entity has hindered the study of a wide range of behaviors. Additionally, the dynamics of HSE-dependent gene expression cannot be simulated accurately by considering the activity of single PKA-RN.

Bibliographic Details

Main Authors:	Pérez Landero, Sergio, Sandoval Motta, Santiago autor/a, Martínez Anaya, Claudia autor/a, Yang, Runying autor/a, Folch Mallol, Jorge Luis autor/a, Martínez, Luz María autor/a, Ventura, Larissa autor/a, Guillén Navarro, Griselda Karina Doctora autor/a 7945, Aldana González, Maximino autor/a, Nieto Sotelo, Jorge autor/a
Format:	Texto biblioteca
Language:	eng
Subjects:	Proteínas quinasas, Levaduras, Fosfatasas cdc25, Análisis genético,
Online Access:	http://www.biomedcentral.com/content/pdf/s12918-015-0185-8.pdf
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