INTEGRATED STRESS RESPONSE, HOW YOUR BODY ADAPTS TO LIFE'S CHALLENGES?

From work pressures to personal challenges, we encounter stress in various forms every day. But did you know that your body has an incredible mechanism to adapt and handle these stressors?

In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis.

By activating the ISR, your body can trigger different mechanisms that boost the quality control of proteins, decrease energy usage, and support cellular repair processes. This, in turn, enhances your capacity to endure and bounce back from stressors.

The ISR can be stimulated by a range of physiological or pathological stimuli including hypoxia, amino acid deprivation, glucose/nutrition deprivation, viral infection and intrinsic endoplasmic reticulum (ER) stress ^(1,3).

Integrated stress response signaling ⁽¹⁾ .

ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2α, the core of ISR. This leads to global attenuation of Cap‐dependent translation while concomitantly initiates the preferential translation of ISR‐specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. It forms homo‐ and heterodimers that bind to DNA targets to control the expression of genes involved in cellular adaptation. Termination of the ISR is regulated by the constitutively expressed CReP and stress‐inducible phosphatase GADD34 that dephosphorylate eIF2α. For more details, see main text and Table 1. Arrows denote activation or induction, while blunt lines indicate inhibition.

THE LINK BETWEEN ISR AND DISEASES

The ISR system plays an important part in the pathophysiology of several disorders such as cancer, cardiovascular system, and neurodegeneration (schizophrenia, amyotrophic lateral sclerosis, head or other nerve trauma) ^(2,4).
Recent studies have shown that ISR activation by salubrinal up-regulates ATF4-modulated gene expression, increases GSH synthesis, and decreases cisplatin-induced oxidative damage, which contribute to cisplatin resistance in gastric cancer cells ⁽⁵⁾.
The integrated stress response (ISR) is a cytoprotective mechanism induced in CNS injuries. Preliminary results indicate that the enhancement of the ISR pathway is a promising therapeutic target for CNS injuries ⁽⁶⁾.

(1) Pakos-Zebrucka K & al. The integrated stress response.. EMBO Rep. (2016); 17(10):1374-1395.

(2) Santos-Ribeiro D & al. The integrated stress response system in cardiovascular disease. Drug Discov Today. (2018); 23(4):920-929.

(3) Wang C & al. Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia. Elife. (2018) 19;7.

(4) Pavitt GD. Regulation of translation initiation factor eIF2B at the hub of the integrated stress response. Wiley Interdiscip Rev RNA. (2018);9(6).

(5) Wang SF & al. Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis. Int J Mol Sci. (2018) 29;19(11).

(6) Romero-Ramírez L& al. Integrated Stress Response as a Therapeutic Target for CNS Injuries. Biomed Res Int. (2017):6953156.

ISR SIGNALING PATHWAY BIOMARKER LIST

You can custom your own SignArrays® with the genes of interest of your choice, according to your project, you just have to download and complete our Personalized SignArrays® information file and send it at [email protected]

You can check the biomarker list included in this pathway, see below:

Species : Homo sapiens (human)

Human Integrated Stress Response

Signaling Pathways	Product ref	Informations
Integrated Stress Response	ISR1H1	List infos

Species : Mus musculus (mouse)

Mouse Integrated Stress Response

Signaling Pathways	Product ref	Informations
Integrated Stress Response	ISR1M1	List infos

Species : Rattus norvegicus (rat)

Rat Integrated Stress Response

Signaling Pathways	Product ref	Informations
Integrated Stress Response	ISR1R1	List infos

Species : Sus Scrofa (Pig)

Pig Integrated Stress Response

Signaling Pathways	Product ref	Informations
Integrated Stress Response	*******	List In progress...

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