Activation of the Akt-CREB signalling axis by a proline-rich heptapeptide confers resistance to stress-induced cell death and inflammation

TY - JOUR

T1 - Activation of the Akt-CREB signalling axis by a proline-rich heptapeptide confers resistance to stress-induced cell death and inflammation

AU - Herkel, Johannes

AU - Schrader, Jörg

AU - Erez, Neta

AU - Lohse, Ansgar W

AU - Cohen, Irun R

N1 - © 2017 John Wiley & Sons Ltd.

PY - 2017/8

Y1 - 2017/8

N2 - Cell stress of various kinds can lead to the induction of cell death and a damaging inflammatory response. Hence, a goal of therapeutic cell-stress management is to develop agents that might effectively regulate undesirable cell death and inflammation. To that end, we developed a synthetic peptide of seven amino acids based on structural mimicry to a functional domain of p53, a key factor in the responses of cells to stressful stimuli. This heptapeptide, which we term Stressin-1, was found to inhibit both cell death and the secretion of inflammatory mediators by various cell types in response to different stressful agents in vitro. The combined anti-inflammatory and anti-apoptotic activities of Stressin-1 were associated with a cellular signalling cascade that induced activation of Akt kinase and activation of the cAMP response element-binding protein (CREB) transcription factor. These immediate signalling events led to the inhibition of the signal transducer and activator of transcription and nuclear factor-κB pathways 24 hr later. Unexpectedly, we found no evidence for a direct involvement of p53 in the effects produced by Stressin-1. Intraperitoneal administration of 100 μg of Stressin-1 to lethally irradiated mice significantly protected them from death. These findings show that activating the Akt-CREB axis with Stressin-1 can counteract some of the undesirable effects of various cell stresses. Stressin-1 may have clinical usefulness.

AB - Cell stress of various kinds can lead to the induction of cell death and a damaging inflammatory response. Hence, a goal of therapeutic cell-stress management is to develop agents that might effectively regulate undesirable cell death and inflammation. To that end, we developed a synthetic peptide of seven amino acids based on structural mimicry to a functional domain of p53, a key factor in the responses of cells to stressful stimuli. This heptapeptide, which we term Stressin-1, was found to inhibit both cell death and the secretion of inflammatory mediators by various cell types in response to different stressful agents in vitro. The combined anti-inflammatory and anti-apoptotic activities of Stressin-1 were associated with a cellular signalling cascade that induced activation of Akt kinase and activation of the cAMP response element-binding protein (CREB) transcription factor. These immediate signalling events led to the inhibition of the signal transducer and activator of transcription and nuclear factor-κB pathways 24 hr later. Unexpectedly, we found no evidence for a direct involvement of p53 in the effects produced by Stressin-1. Intraperitoneal administration of 100 μg of Stressin-1 to lethally irradiated mice significantly protected them from death. These findings show that activating the Akt-CREB axis with Stressin-1 can counteract some of the undesirable effects of various cell stresses. Stressin-1 may have clinical usefulness.

KW - Animals

KW - Cell Death

KW - Cell Line

KW - Cyclic AMP

KW - Cyclic AMP Response Element-Binding Protein

KW - Humans

KW - Inflammation

KW - Macrophages

KW - Mice

KW - Molecular Mimicry

KW - NF-kappa B

KW - Oncogene Protein v-akt

KW - Peptide Fragments

KW - Proline

KW - STAT Transcription Factors

KW - Signal Transduction

KW - Stress, Physiological

KW - Tumor Suppressor Protein p53

KW - Journal Article

U2 - 10.1111/imm.12745

DO - 10.1111/imm.12745

M3 - SCORING: Journal article

C2 - 28419468

VL - 151

SP - 474

EP - 480

JO - IMMUNOLOGY

JF - IMMUNOLOGY

SN - 0019-2805

IS - 4

ER -