Farnesol induces ER stress and activation of the unfolded protein response

Farnesol induces ER stress and activation of the unfolded protein response. Activation of the MEK-ERK signaling pathway by farnesol is an early event that is critical in triggering the UPR. The UPR is initiated by the activation of several ER stress-sensor proteins, including PERK, IRE1, and ATF6. Dissociation of the ER chaperone BiP/GRP78 from UPR sensor protein complexes plays a critical role in their activation. Release of BiP leads to activation and nuclear translocation of ATF6. Activation of PERK results in the phosphorylation of eIF2α and subsequently to an attenuation of the rate of general mRNA translation and protein synthesis. However, it selectively enhances the translation of some mRNAs, including the transcription factor ATF4. Active IRE1 induces alternative splicing of XBP1 mRNA resulting in the synthesis of a potent transcriptional activator. ATF4, ATF6, and XBP1 enhance the transcription of several chaperones. Activation of these pathways lead to inhibition of newly synthesized protein, increased degradation of misfolded proteins, and amplification of the protein folding capacity with the intend to restore normal ER function and promote cell survival. If ER homeostasis cannot be restored, cells start to undergo apoptosis. The IRE1-TRAF2-ASK1-JNK cascade is an important pro-apoptotic signaling pathway in ER stress. GRPs, glucose response proteins; SRPs, stress response proteins; PARP, poly(ADP-ribose) polymerase

Publication

Molecular Mechanisms involved in Farnesol-Induced Apoptosis. () Joung Hyuck Joo, et al. Cancer Lett. ;287(2):123. Figure: F3. All organisms Mus musculus Homo sapiens Rattus norvegicus Cricetulus griseus Mesocricetus auratus Drosophila melanogaster

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