Caspase-9 is activated in a cytochrome c-independent manner early during TNFα-induced apoptosis in murine cells
Abstract
FL5.12 pro-B lymphoma cells utilize the mitochondrial pathway to apoptosis in response to tumor necrosis factor (TNF) receptor occupation, yet high levels of the Bcl-2 family antiapoptotic protein, Bcl-x(L), fail to protect these cells against TNF-receptor-activated death. Bcl-x(L) expression delays, but does not totally block, the release of mitochondrial cytochrome c (cyt c) in these cells in response to TNFalpha-induced apoptosis and caspase-9 is processed prior to mitochondrial cyt c release under these circumstances. Early processing of caspase-9 also occurred in Apaf-1 knockout murine fibroblasts in response to TNF-receptor occupation. A caspase-9-specific inhibitor was more effective in delaying the progression of apoptosis in the FL5.12 Bcl-x(L) cells than was an inhibitor specific to caspase-3. Furthermore, downregulation of caspase-9 levels by RNA interference resulted in partial protection of these cells against TNF-receptor-activated apoptosis, indicating that caspase-9 activation contributed to early amplification of the caspase cascade. Consistent with this, proteolytic processing of caspase-9 was observed prior to processing by caspase-3, suggesting that caspase-3 was not responsible for early caspase-9 activation. We show that murine caspase-9 is efficiently processed by active caspase-8 at SEPD, the motif at which caspase-9 autoprocesses following its recruitment to the apoptosome. Our results suggest that, in addition to processing procaspase-3 and the BH3 protein Bid, active caspase-8 can cleave and activate procaspase-9 in response to TNF receptor crosslinking in murine cells.
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CASP9 downregulation is anti-apoptotic and protective against TNF-receptor-activated apoptosis.
“CASP9 (FC = −1.28, p = 0.026) is an initiator in the apoptotic pathway, and so its downregulation is both anti-apoptotic and protective against TNF-receptor-activated apoptosis [93].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [93]
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- Authors
- McDonnell, M. A., Wang, D., Khan, S. M., Vander Heiden, M. G., & Kelekar, A.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Kelekar, A
- Venue
- Cell Death & Differentiation
- Published
- 2003-08-22
- Volume
- 10
- Issue
- 9
- Pages
- 1005-1015
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- OpenAlex
- W2003939380
- Cited by
- 109
- References
- 42
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 1 · 2019: 3 · 2018: 6 · 2017: 8 · 2016: 4 · 2015: 6 · 2014: 3 · 2013: 4 · 2012: 3
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Keywords
- caspase-9, TNF-induced apoptosis, caspase-8, Bcl-xL, caspase-3, caspase cascade, TNF receptor signaling, Apaf-1, Bid
- MeSH terms
- Amino Acid Sequence, Animals, B-Lymphocytes, Enzyme Activation, Kinetics, Mitochondria, Molecular Sequence Data, Proteins, Stem Cells, Tumor Necrosis Factor-alpha, Sequence Alignment, Apoptosis, Receptors, Tumor Necrosis Factor, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, Caspases, RNA Interference, Cytochromes c, Cell Line, Tumor, bcl-X Protein, Mice, Caspase 8, Caspase 9, Apoptotic Protease-Activating Factor 1
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