ArticleMolecular cell2011
Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop.
Article in Molecular cell, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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Who cites it
100 citing papers in PubMed, 162 citations in OpenAlex.
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- Caspase-2 kills cells with extra centrosomes.Science advances · 2024Article
- Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.Science advances · 2024Article
- Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors.Journal of the American Chemical Society · 2024Article
- Ketogenic diet induces p53-dependent cellular senescence in multiple organs.Science advances · 2024Article
- Caspase-2 protects against ferroptotic cell death.Cell death & disease · 2024Article
- Inhibiting centrosome clustering reduces cystogenesis and improves kidney function in autosomal dominant polycystic kidney disease.JCI insight · 2024Article
- Inhibition of OCT4 binding at theFrontiers in oncology · 2024Article
- A Cell-Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer-Specific Synthetic Lethality.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Tumor suppressor p53 mediates interleukin-6 expression to enable cancer cell evasion of genotoxic stress.Cell death discovery · 2023Article
- Cellular polyploidy in organ homeostasis and regeneration.Protein & cell · 2023Article
- BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors.Molecular cancer · 2023Article
- Targeting caspase-2 interactions with tau in Alzheimer's disease and related dementias.Translational research : the journal of laboratory and clinical medicine · 2023Review
- Expanding roles of centrosome abnormalities in cancers.BMB reports · 2023Review
- When cell death goes wrong: inflammatory outcomes of failed apoptosis and mitotic cell death.Cell death and differentiation · 2023Review
- Genuine selective caspase-2 inhibition with new irreversible small peptidomimetics.Cell death & disease · 2022Article
40 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress.
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