Related Experiment Video

Updated: Apr 28, 2026

Evaluation of Caspase Activation to Assess Innate Immune Cell Death
10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

3.6K

Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis

Fabian Treude1, Ferdinand Kappes, Dirk Fahrenkamp

  • 1Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany.

Oncotarget
|June 17, 2014
PubMed

Insights

Prostate apoptosis response-4 (PAR-4) protein cleavage by caspase-8 is essential for its tumor-suppressing activity. This controlled PAR-4 fragmentation triggers apoptosis, offering a new therapeutic target for cancer treatment.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor protein PAR-4 is downregulated in cancers, aiding cancer cell survival.
  • PAR-4 re-expression induces apoptosis in cancer cells, but its precise control mechanism is unknown.

Purpose of the Study:

  • To elucidate the mechanism controlling PAR-4's pro-apoptotic function.
  • To investigate the role of PAR-4 cleavage in UV- and TNFα-induced apoptosis.

Main Methods:

  • Generated stable cell lines expressing wild-type PAR-4 or a cleavage-resistant mutant (PAR-4 D131G) using a doxycycline-inducible promoter.
  • Utilized UV and TNFα to induce apoptosis and analyzed PAR-4 cleavage.
  • Assessed the impact of PAR-4 expression and cleavage on cell proliferation and apoptosis.

Main Results:

  • UV-induced apoptosis resulted in rapid, caspase-dependent cleavage of PAR-4 at EEPD131G, preferentially recognized by caspase-8.
  • Induction of wild-type PAR-4, but not the D131G mutant, inhibited cell proliferation via apoptosis.
  • TNFα-induced apoptosis involved caspase-8-dependent PAR-4 cleavage, leading to nuclear accumulation of the C-terminal fragment (132-340) and subsequent apoptosis.

Conclusions:

  • PAR-4 cleavage by caspase-8 is a critical step in its apoptotic function.
  • This cleavage event is essential for PAR-4 to induce apoptosis and inhibit cancer cell proliferation.
  • The findings reveal a novel mechanism for PAR-4-mediated apoptosis, highlighting caspase-8 as a key regulator.

More Related Videos

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry05:29

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry

Published on: March 24, 2023

7.7K
Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex07:17

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex

Published on: August 2, 2021

2.1K

Related Concept Videos

The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

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...
6.1K
Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
8.6K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

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...
6.2K
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size...
12.0K
Phagocytosis of Apoptotic Cells01:17

Phagocytosis of Apoptotic Cells

Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or  immature dendritic cells. Non-professional phagocytes such as  epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes. 
Normal cells contain receptors that prevent them from being recognized...
3.9K
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
7.4K