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Related Concept Videos

Necrosis01:16

Necrosis

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Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
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The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
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Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
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RIP3/MLKL regulates necroptosis via activating 4EBP1-eIF4E pathway.

Shuchao Wang1, Meili Xu2

  • 1Center for Medical Research, Second Xiangya Hospital, Central South University, Changsha 410011. wangshuchao@csu.edu.cn.

Zhong Nan Da Xue Xue Bao. Yi Xue Ban = Journal of Central South University. Medical Sciences
|September 19, 2023
PubMed
Summary

The eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1)-eukaryotic initiation factor 4E (eIF4E) pathway is activated during receptor interacting protein 3 (RIP3)/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. This study investigated the role of this pathway in necroptosis.

Keywords:
eukaryotic initiation factor 4Eeukaryotic translation initiation factor 4E-binding protein 1mixed lineage kinase domain-like proteinnecroptosisreceptor interacting protein 3

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Necroptosis is a regulated form of cell death.
  • Receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL) mediate necroptosis.
  • The mammalian target of rapamycin (mTOR) pathway regulates necroptosis via the eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1)-eukaryotic initiation factor 4E (eIF4E) axis.

Purpose of the Study:

  • To investigate the involvement of the 4EBP1-eIF4E pathway in necroptosis.
  • To determine the changes in 4EBP1 and eIF4E expression during RIP3/MLKL-mediated necroptosis.

Main Methods:

  • Necroptosis was induced in L929 cells using TNF-α/SM-164/Z-VAD-FMK (TSZ).
  • RIP3 and MLKL gene knockout L929 cells were used to confirm specificity.
  • Cell necrosis was assessed via optical microscopy and propidium iodide (PI) staining.
  • mRNA and protein expression of 4EBP1 and eIF4E were quantified using real-time PCR and Western blotting.

Main Results:

  • TSZ treatment increased necroptosis, downregulated 4EBP1, and upregulated eIF4E.
  • Phosphorylation of 4EBP1 and eIF4E increased upon necroptosis induction.
  • In RIP3/MLKL knockout cells, necroptosis was reduced, 4EBP1 expression increased, and eIF4E expression decreased.

Conclusions:

  • The 4EBP1-eIF4E pathway is activated during RIP3/MLKL-mediated necroptosis.
  • This pathway plays a significant role in the necroptotic process.