p21

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p21
© 2020 PFPC

p21 is also known as WAF1, CIP1, SDI1, and MDA-6. It is a cyclin kinase (CDK) inhibitor (Gartell et al., 1994).

p21 levels increase following the activation of p53 (Mansilla et al., 2020). In COVID-19, the lung damage observed is thought to be the result of apoptosis via P53 signalling pathway in lymphocytes (Xiong et al., 2020).

COVID-19

Re: chloroquine (CQ)

"In 2016, a Korean team found that the CQ up-regulates p21 (a CDK inhibitor) whose expression is suppressed by PAK1 [3,6]."

Maruta H, He H - "PAK1-blockers: Potential Therapeutics against COVID-19" Med Drug Discov 100039 (2020) doi: 10.1016/j.medidd.2020.100039. Epub ahead of print. PMID: 32313880; PMCID: PMC7166201.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166201/

Fluoride:

"Fluoride overexposure is an environmental health hazard and can cause enamel and skeletal fluorosis. Previously we demonstrated that fluoride increased acetylated-p53 and its downstream target p21 in ameloblast-derived LS8 cells.... Inhibition of MDM2-mediated p21 degradation may be a potential therapeutic target to mitigate fluoride toxicity."

Deng H, Ikeda A, Cui H, Bartlett JD, Suzuki M - "MDM2-Mediated p21 Proteasomal Degradation Promotes Fluoride Toxicity in Ameloblasts" Cells 10;8(5):436 (2019) doi: 10.3390/cells8050436. PMID: 31083332; PMCID: PMC6562432.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562432/

"The results showed a positive relationship between fluoride exposure and expression of Cyclin d1/CDK4, and a negative relationship between fluoride exposure and expression of P21."

Pan X, Yan W, Qiu B, Liao Y, Liao Y, Wu S, Ming J, Zhang A - "Aberrant DNA methylation of Cyclind-CDK4-p21 is associated with chronic fluoride poisoning" Chem Biol Interact 315:108875 (2020) doi: 10.1016/j.cbi.2019.108875. Epub 2019 Oct 25. PMID: 31669217.
https://pubmed.ncbi.nlm.nih.gov/31669217/

Suzuki M, Ikeda A, Bartlett JD - " Sirt1 overexpression suppresses fluoride-induced p53 acetylation to alleviate fluoride toxicity in ameloblasts responsible for enamel formation" Arch Toxicol 92(3):1283-1293 (2018) doi: 10.1007/s00204-017-2135-2. Epub 2017 Nov 28. PMID: 29185024; PMCID: PMC6667832.

Gq/11

"In addition to its well known involvement in Gq/11-mediated vasoconstriction and its key roles in the homeostasis of electrolyte balances, the angiotensin II type 1 (AT1) receptor activates mitogen-activated protein kinase (MAPK) and p42/44 extracellular signal-regulated kinase. The extracellular signal-regulated kinase activation is mediated by activation of p21-Ras, Raf-1, and MAPK kinase in rat vascular smooth muscle cells.

Inagami T, Eguchi S, Numaguchi K, et al - "Cross-talk between angiotensin II receptors and the tyrosine kinases and phosphatases" J Am Soc Nephrol 10 Suppl 11:S57‐S61 (1999)
https://pubmed.ncbi.nlm.nih.gov/9892141/

Coronavirus:
Lv X, Li Z, Guan J, et al. - "Porcine Hemagglutinating Encephalomyelitis Virus Activation of the Integrin α5β1-FAK-Cofilin Pathway Causes Cytoskeletal Rearrangement To Promote Its Invasion of N2a Cells" J Virol 93(5):e01736-18 (2019) Published 2019 Feb 19. doi:10.1128/JVI.01736-18
https://pubmed.ncbi.nlm.nih.gov/30541856/
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Gartel AL, Serfas MS, Tyner AL - "p21--negative regulator of the cell cycle" Proc Soc Exp Biol Med 213(2):138-49 (1996) doi: 10.3181/00379727-213-44046. PMID: 8931660
https://pubmed.ncbi.nlm.nih.gov/8931660/

Mansilla SF, de la Vega MB, Calzetta NL, Siri SO, Gottifredi V - "CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication" Genes (Basel). 2020 11(6):E593 (2020) doi: 10.3390/genes11060593. PMID: 32481484
https://pubmed.ncbi.nlm.nih.gov/32481484/

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New paper on p53/Spike

Zhang S, El-Deiry W - "SARS-CoV-2 spike S2 subunit inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells"
https://www.biorxiv.org/content/10.1101 ... 2.589252v1

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. We examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells. We further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike S2-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike S2 were found to have increased cell viability as compared to control cells. Further observations on gamma-H2AX expression in spike S2-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics.

Competing Interest Statement

W.S.E-D. is a co-founder of Oncoceutics, Inc., a subsidiary of Chimerix, p53-Therapeutics, Inc. and SMURF-Therapeutics, Inc. Dr. El-Deiry has disclosed his relationships and potential conflicts of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest.