Protein stress responses that engage the unfolded protein response (UPR) during ER-induced stress may antagonize cell death or eventually lead to apoptosis. In the ER, over a third of all cellular proteins undergo processing, including protein folding, posttranslational manipulations, and structural maturation. Despite the robustness of the ER machinery, cells often function at the limit of their secretory capacity, and a wide variety of conditions can disrupt protein folding and result in the accumulation of misfolded proteins, known as ER stress. These triggers include nutrient deprivation, hypoxia, ROS accumulation, and loss of calcium homeostasis. The UPR engages three key signaling stressors located in the ER: PKR-like ER kinase (PERK), IRE1 (α and β), and activating transcription factor-6 (ATF6, α and β). These pathways regulate transcription of genes involved in resolving ER stress but also induce transcription of genes involved in apoptosis, causing the death of cells that are unable to manage the stress. Activation of PERK through autophosphorylation inhibits protein translation through the phosphorylation of eukaryotic translation initiator factor-2 (eIF2α) at serine 51, which also represents a convergence point for the so-called integrated stress response. eIF2α phosphorylation reduces the overall protein load but simultaneously induces mRNA translation of the transcription factor ATF4, which increases the antioxidant response and ER folding capacity and may also trigger macroautophagy. ATF4 also regulates the expression of genes involved in apoptosis, including the transcription factors TP53, C/EBP-homologous protein (CHOP), and growth arrest and DNA damage-inducible 34 (GADD34). CHOP inhibits expression of the antiapoptotic BCL2 and induces that of proapoptotic proteins such as BIM and NOXA. IRE1α is a transmembrane protein that, in response to unfolded proteins, catalyzes splicing of the XBP1 transcription fac tor, which in turn regulates transcription of genes involved in protein folding, secretion, and translocation. The second functional output of IRE1α is degradation of multiple mRNAs, microRNAs, and rRNAs in the cytosol and ER through a process called regulated IRE1 dependent decay, or RIDD, which is mediated by the RNase cytosolic domain of IRE1α. The RIDD function of IRE1α degrades specific microRNAs that affect the translation of caspase-2 to induce apoptosis via BID. ATF6α is also an ER transmembrane protein that, under ER stress, undergoes cleavage and releases its cytosolic domain containing transcription factor, ATF6f, which causes transcription of genes that regulate ER-associated degradation of unfolded proteins.

Emerging evidence from multiple experimental systems indicates that select protein modulators of UPR can promote either cell survival or cell death, depending on the extent of ER damage or the duration of UPR. Recent data indicate the important role of UPR in the regulation of the cancer-associated processes of metastasis, angiogenesis, and chemoresistance. Although it remains to be determined whether agents targeting UPR regulators could be used as cancer therapeutics, recent studies have reported preclinical efficacy of small molecules that inhibit PERK or IRE1a in cancer models.

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قسم صناعة الشبابيك يشرع بإدامة شباكين قديمين لمرقد الإمامين العسكريين (عليهما السلام)

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العتبة العسكرية المقدسة تكرّم وفد العتبة العباسية المقدسة لمشاركته في تقديم الخدمات للزائرين

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الآخبار الصحية

كنز غذائي على طبقك.. ماذا تفعل السبانخ بجسمك؟

ما لا يتوقعه أحد.. "سر غذائي" في الجبن الدسم

لتحسين الهضم والنوم.. هذا أفضل وقت لتناول العشاء

10 طرق بسيطة وغير مألوفة لحرق المزيد من السعرات يوميا

المزيد

الآخبار التكنلوجية

سابقة بعالم الطيران.. طائرة تقرر الهبوط بنفسها بعد ظرف طارئ

"الإنفلونزا الخارقة" تكتسح دول العالم.. وتثير قلقا كبيرا

مرحلة ما قبل الأعراض.. دواء جديد يستهدف "شرارة" الزهايمر

إزالة ثاني أكسيد الكربون من الغلاف الجوي.. ما دور المحيطات والبحار؟

المزيد

مواضيع ذات صلة

Autophagy

Nonapoptotic forms of cell death

The Cell Division Cycle

Stem Cells

Proliferation and the Cell Cycle

Growth Factors and Receptors

Signal Transduction Pathways

Cell Signaling

Cellular Metabolism and Mitochondrial Function

Waste Disposal: Lysosomes and Proteasomes

Biosynthetic Machinery: Endoplasmic Reticulum and Golgi

Cytoskeleton and Cell-Cell Interactions