WISP1 Neuroprotection Requires FoxO3a Post-Translational Modulation with Autoregulatory Control of SIRT1
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As a member of the secreted extracellular matrix associated proteins of the CCN family, Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4) is garnering increased attention not only as a potent proliferative entity, but also as a robust cytoprotective agent during toxic insults. Here we demonstrate that WISP1 prevents forkhead transcription factor FoxO3a mediated caspase 1 and caspase 3 apoptotic cell death in primary neurons during oxidant stress. Phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt1) are necessary for WISP1 to foster posttranslational phosphorylation of FoxO3a and sequester FoxO3a in the cytoplasm of neurons with protein 14-3-3. Through an autoregulatory loop, WISP1 also minimizes deacytelation of FoxO3a, prevents caspase 1 and 3 activation, and promotes an effective neuroprotective level of SIRT1 activity through SIRT1 nuclear trafficking and prevention of SIRT1 caspase degradation. Elucidation of the critical pathways of WISP1 that determine neuronal cell survival during oxidative stress may offer novel therapeutic avenues for neurodegenerative disorders.
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WISP1 has been shown to be protective against oxidative stress in neurons and to block amyloid toxicity in inflammatory microglia of the brain.
“WISP1 has been shown to be protective against oxidative stress in neurons [10–12] and to block amyloid toxicity in inflammatory microglia of the brain [13].”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [12]
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Self-citationForkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss
Maiese, K. (2017) · Current Neurovascular Research · doi:10.2174/1567202614666171116102911 · Cited by 56 · see citing works
Self-citationRegeneration in the nervous system with erythropoietin
Maiese, K. (2015) · Frontiers in bioscience · doi:10.2741/4408 · Cited by 55 · see citing works
Self-citationErythropoietin and diabetes mellitus
Maiese, K. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i14.1259 · Cited by 55 · see citing works
Self-citationWang, J., Zheng, X., Zeng, G., Zhou, Y., & Yuan, H. (2013) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2013.1587 · Cited by 49 · see citing works
Maiese, K. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1273570 · Cited by 47 · see citing works
Self-citationIdentification of Molecular Pathways Facilitating Glioma Cell Invasion In Situ
Nevo, I., Woolard, K., Cam, M. C., Li, A., Webster, J. D., Kotliarov, Y., Kim, H. S., Ahn, S. J., Walling, J., Kotliarova, S. E., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111783 · Cited by 44 · see citing works
Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease
Maiese, K. (2016) · Current Neurovascular Research · doi:10.2174/1567202613666161129112822 · Cited by 44 · see citing works
Self-citationProgramming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus
Maiese, K. (2015) · Current Neurovascular Research · doi:10.2174/1567202612666150305110929 · Cited by 43 · see citing works
Self-citationCircRNAs in the tree shrew (Tupaia belangeri) brain during postnatal development and aging
Lü, C., Sun, X., Li, N., Wang, W., Kuang, D., Tong, P., Han, Y., & Dai, J. (2018) · Aging · doi:10.18632/aging.101437 · Cited by 43 · see citing works
Wang, Y., Gao, S., Zheng, V., Chen, L., Ma, M., Shen, S., Qu, J., Zhang, H., Gurney, M. E., O’Donnell, J. M., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.599389 · Cited by 41 · see citing works
Tank, J., Lindner, D., Wang, X., Stroux, A., Gilke, L., Gast, M., Zietsch, C., Skurk, C., Scheibenbogen, C., Klingel, K., et al. (2013) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2013.11.004 · Cited by 38 · see citing works
MicroRNAs and SIRT1: A Strategy for Stem Cell Renewal and Clinical Development?
Maiese, K. (2016) · Journal of Translational Science · doi:10.15761/jts.1000112 · Cited by 39 · see citing works
Self-citationProspects and Perspectives for WISP1 (CCN4) in Diabetes Mellitus
Maiese, K. (2020) · Current Neurovascular Research · doi:10.2174/1567202617666200327125257 · Cited by 37 · see citing works
Self-citationHe, W., Lu, Q., Sherchan, P., Huang, L., Hu, X., Zhang, J. H., Dai, H., & Tang, J. (2021) · Fluids and Barriers of the CNS · doi:10.1186/s12987-021-00278-9 · Cited by 37 · see citing works
Sirtuins: Developing Innovative Treatments for Aged-Related Memory Loss and Alzheimer’s Disease
Maiese, K. (2018) · Current Neurovascular Research · doi:10.2174/1567202616666181128120003 · Cited by 36 · see citing works
Self-citationGhoneum, M. H., & Sayed, N. S. E. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/8845064 · Cited by 35 · see citing works
Labrousse-Arias, D., Martı́nez-Ruiz, A., & Calzada, M. J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7275 · Cited by 31 · see citing works
Angiokine Wisp-1 is increased in myocardial infarction and regulates cardiac endothelial signaling
Wright, L. H., Herr, D. J., Brown, S. S., Kasiganesan, H., & Menick, D. R. (2018) · JCI Insight · doi:10.1172/jci.insight.95824 · Cited by 31 · see citing works
Cognitive Impairment in Multiple Sclerosis
Maiese, K. (2023) · Bioengineering · doi:10.3390/bioengineering10070871 · Cited by 30 · see citing works
Self-citationMaiese, K. (2023) · Cells · doi:10.3390/cells12222595 · Cited by 28 · see citing works
Self-citationJenwitheesuk, A., Park, S., Wongchitrat, P., Tocharus, J., Mukda, S., Shimokawa, I., & Govitrapong, P. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2369-7 · Cited by 24 · see citing works
Yang, X., Dong, W., Lei, X., Li, Q., Zhang, L.-Y., & Zhang, L. (2017) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767058.2017.1311310 · Cited by 20 · see citing works
Dual effect of WISP-1 in diverse pathological processes
Feng, M., & Jia, S. (2016) · Chinese Journal of Cancer Research · doi:10.21147/j.issn.1000-9604.2016.06.01 · Cited by 19 · see citing works
The Effect of Pyrroloquinoline Quinone on the Expression of WISP1 in Traumatic Brain Injury
Ye, Y., Zhang, P., Qian, Y., Yin, B., & Yan, M. (2017) · Stem Cells International · doi:10.1155/2017/4782820 · Cited by 16 · see citing works
Liu, L., Xu, S., Li, P., & Li, L. (2022) · Obesity Research & Clinical Practice · doi:10.1016/j.orcp.2022.03.001 · Cited by 15 · see citing works
Christopoulou, M. E., Aletras, A. J., Papakonstantinou, E., Stolz, D., & Skandalis, S. S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251810049 · Cited by 19 · see citing works
Healing the Heart with Sirtuins and Mammalian Forkhead Transcription Factors
Maiese, K. (2019) · Current Neurovascular Research · doi:10.2174/1567202616999191209142915 · Cited by 13 · see citing works
Self-citationWu, Z., Ai, X., Hu, H., Wang, S., Wang, Y., Feng, K., Ouyang, C., & Zhu, J. (2019) · Cancer Biology & Therapy · doi:10.1080/15384047.2019.1617562 · Cited by 11 · see citing works
Self-citationInnovative therapeutic strategies for cardiovascular disease
Maiese, K. (2023) · EXCLI journal · doi:10.17179/excli2023-6306 · Cited by 9 · see citing works
Self-citationSalmina, A. B., Анатольевна, Я. Н., Kuvacheva, N. V., Петрова, М. М., Taranushenko, T. Y., Malinovskaya, N. A., Lopatina, O. L., Morgun, A. V., Pozhilenkova, Y. A., Сергеевна, О. О., et al. (2013) · Bulletin of Siberian Medicine · doi:10.20538/1682-0363-2013-5-104-118 · Cited by 9 · see citing works
Gul, M. T., Khattak, M. N. K., Qaisar, R., Jayakumar, M. N., Samsudin, A. B. R., & Khan, A. A. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04702-1 · Cited by 4 · see citing works
Maiese, K. (2026) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2026.2671269 · Cited by 5 · see citing works
Self-citationNovel treatment strategies for neurodegenerative disease with sirtuins
Maiese, K. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-814118-2.00001-x · Cited by 3 · see citing works
Self-citationLiu, L.-C., Xu, S., & Li, L. (2021) · International Journal of Diabetes in Developing Countries · doi:10.1007/s13410-021-00972-2 · Cited by 1 · see citing works
Novel Pathways of Autophagy for the Treatment of Nervous System Disorders
Maiese, K. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-805253-2.00016-x
Self-citationWang, H., Lazarovici, P., & Zheng, W. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_101601
Wang, H., Lazarovici, P., & Zheng, W. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6438-9_101601-1
He, W., Lu, Q., Sherchan, P., Huang, L., Hu, X., Zhang, J. H., Dai, H., & Tang, J. (2021) · Figshare · doi:10.6084/m9.figshare.16682832
He, W., Lu, Q., Sherchan, P., Huang, L., Hu, X., Zhang, J. H., Dai, H., & Tang, J. (2021) · Figshare · doi:10.6084/m9.figshare.16682838
He, W., Lu, Q., Sherchan, P., Huang, L., Hu, X., Zhang, J. H., Dai, H., & Tang, J. (2021) · Figshare · doi:10.6084/m9.figshare.16682835
Maiese, K. (2026) · Antioxidants · doi:10.3390/antiox15070895 · Cited by 1 · see citing works
Self-citationRunning out the clock: Circadian rhythm dysfunction in cognitive disease
Maiese, K. (2026) · International review of neurobiology · doi:10.1016/bs.irn.2026.08.015 · Cited by 1 · see citing works
Self-citation
- Authors
- Wang, S., Zhong Chong, Z., Chen Shang, Y., & Maiese, K.
- Affiliations
- Rutgers Cancer Institute (US)
- Corresponding author
- Maiese, Kenneth
- Venue
- Current Neurovascular Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2013-02-01
- Volume
- 10
- Issue
- 1
- Pages
- 54-69
- ISSN
- 1567-2026 (ISSN-L)
- PMC
- PMC3568221
- OpenAlex
- W2099032267
- Cited by
- 58
- References
- 84
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 7 · 2020: 2 · 2019: 2 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 10 · 2014: 3 · 2013: 4
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Current Neurovascular Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- American Heart Association
- National Institutes of Health
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke (R01NS053946)
- National Institute of Environmental Health Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- 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
- Keywords
- FOXO3, SIRT1, neuroprotection, oxidative stress, apoptosis, caspase-1, caspase-3, PI3K/Akt signaling, post-translational phosphorylation, deacylation, autoregulatory loop, nuclear trafficking, CCN family proteins, neurodegenerative diseases, neurons
- MeSH terms
- Forkhead Box Protein O3, Resveratrol, Wortmannin, Androstadienes, Cell Survival, Chromones, Enzyme Inhibitors, Heterocyclic Compounds, 4 or More Rings, Hippocampus, Homeostasis, Humans, Morpholines, Neurons, Phosphorylation, Proto-Oncogene Proteins, Stilbenes, Signal Transduction, Cell Hypoxia, Oxidative Stress, Forkhead Transcription Factors, Caspase 3, CCN Intercellular Signaling Proteins, Sirtuin 1
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