WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase
Open accessAbstract
WISP-1 (W nt-1-i nduced s ecreted p rotein) was identified as an oncogene regulated by the Wnt-1–β-catenin pathway. WISP-1 belongs to the CCN family of growth factors, which are cysteine-rich, heparin-binding, secreted proteins associated with the extracellular matrix, and can interact with cellular integrins. Expression of WISP-1 in some cells results in transformation and tumorigenesis. Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. It also is demonstrated that WISP-1 can prevent cells from undergoing apoptosis following DNA damage through inhibition of the mitochondrial release of cytochrome c and up-regulation of antiapoptotic Bcl-X L. Furthermore, the results show that WISP-1 protects cells from p53-dependent cell death, but not Fas-ligand activated cell death, suggesting that there may be cross talk between the tumor suppressor protein p53 and WISP-1 signaling pathways. WISP-1 acts to block cell death at a late stage in the p53-mediated apoptosis pathway.
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WISP1 promotes cytoprotection in multiple cell types through pathways that require PI 3-K and Akt and, in microglia, involve mTOR and PRAS40.
“WISP1 promotes cytoprotection in multiple cell types through pathways that not only require phosphatidylinositol-3-kinase (PI 3-K) and protein kinase B (Akt) [7, 8, 10, 11, 20, 21], but also utilize pathways in microglia that involve the mammalian target of rapamycin (mTOR) and the proline rich Akt substrate 40 kDa (PRAS40) [13].”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [7]
The section ‘WISP-1 inhibition of apoptosis requires Akt activity’ (page unavailable) reports that blocking Akt attenuated WISP-1’s protection against DNA-damage-induced apoptosis in H460 cells. The paper supports an Akt-dependent protective effect in that setting, but does not establish that PI 3-K is required or that the effect occurs across multiple cell types. The microglial mTOR/PRAS40 mechanism is separately attributed to citation [13], not this source. (LLM, conf=0.87)
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References 72 · Cited by 153
Research works printed but not linked: 6
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- Authors
- Su, F., Overholtzer, M., Besser, D., & Levine, A. J.
- Affiliations
- Rockefeller University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2002-01-01
- Volume
- 16
- Issue
- 1
- Pages
- 46-57
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC155313
- OpenAlex
- W2106798509
- Cited by
- 153
- References
- 72
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 2 · 2021: 9 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 12 · 2014: 9 · 2013: 6 · 2012: 12
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Susan G. Komen for the Cure
- National Institutes of Health (CA87497)
- National Cancer Institute (CA-87497, P01CA087497)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- WISP1, CCN family, p53, apoptosis, DNA damage, Akt kinase, anti-apoptotic signaling, cytochrome c release, Bcl-xL, Fas ligand, cell death
- MeSH terms
- Animals, Cell Line, Cytochrome c Group, Growth Substances, Humans, Proto-Oncogene Proteins, Signal Transduction, Oncogene Proteins, Tumor Suppressor Protein p53, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Intracellular Signaling Peptides and Proteins, bcl-X Protein, CCN Intercellular Signaling Proteins
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