Upregulation of p21(WAF1/Cip1) precedes tumor necrosis factor-induced necrosis-like cell death

Related Experiment Video

Updated: Aug 9, 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

Sandra Ussat1, Ulf-Eike Werner, Marie-Luise Kruse

  • 1Institut für Immunologie, Christian-Albrechts-Universität Kiel, Michaelisstrasse 5, Kiel D-24105, Germany.

Biochemical and Biophysical Research Communications
|June 12, 2002
PubMed

Insights

Tumor necrosis factor triggers necrotic cell death via p21(WAF1/Cip1) upregulation, a process influenced by cell cycle progression. Inhibiting p21(WAF1/Cip1) enhances this necrotic cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Caspase-independent necrotic cell death mechanisms are not fully understood.
  • NIH3T3 cells show sensitization to death receptor-induced cytotoxicity with caspase inhibition, leading to necrosis-like cell death.
  • Cell cycle progression plays a role in this sensitization effect.

Purpose of the Study:

  • To investigate the molecular mechanisms of tumor necrosis factor-induced necrotic cell death.
  • To elucidate the role of p21(WAF1/Cip1) and cell cycle progression in this process.

Main Methods:

  • Upregulation of p21(WAF1/Cip1) was assessed in NIH3T3 cells treated with tumor necrosis factor.
  • The functionality of p21(WAF1/Cip1) was examined through its nuclear localization and binding to cyclin-dependent kinases.
  • Pharmacological inhibitors were used to explore the involvement of p38 mitogen-activated protein kinase.
  • The effect of p21(WAF1/Cip1) inhibition on cell cycle progression and cell death was analyzed.

Main Results:

  • Tumor necrosis factor-induced necrotic death is preceded by increased expression of p21(WAF1/Cip1).
  • p21(WAF1/Cip1) upregulation occurs in the nucleus, indicating functional activity.
  • p38 mitogen-activated protein kinase partially contributes to p21(WAF1/Cip1) upregulation.
  • Inhibition of p21(WAF1/Cip1) upregulation prevents G2/M cell cycle delay and augments cell death.

Conclusions:

  • p21(WAF1/Cip1) upregulation is a key event in tumor necrosis factor-induced necrotic cell death.
  • The interplay between p21(WAF1/Cip1), cell cycle progression, and necrotic cell death is crucial.
  • Targeting p21(WAF1/Cip1) may offer therapeutic strategies for enhancing necrotic cell death in cancer treatment.

More Related Videos

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System08:15

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System

Published on: April 11, 2025

LPS and ATP-induced Death of PMA-differentiated THP-1 Macrophages and its Validation06:12

LPS and ATP-induced Death of PMA-differentiated THP-1 Macrophages and its Validation

Published on: May 3, 2024

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
Overview of Cell Death01:30

Overview of Cell Death

Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...
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...
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...
Necrosis01:16

Necrosis

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”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...