Mechanisms involved in mutant p53 exerting GOF effects

Mechanisms involved in mutant p53 exerting GOF effects. (A) The functional modes involved in mutant p53 exerting GOF effects. I) Mutant p53 binds novel sites to induce transactivation of target genes. II) Mutant p53 interacts with other TFs to induce transactivation of target genes. III) Mutant p53 inhibits other TFs via protein-protein interactions to disrupt the expression of genes targeted by those TFs. (B) The effects of GOF produced by mutant p53 in tumors. The triple complex formed by NF-Y, mutant p53 and P300 proteins can promote the expression of NF-Y target genes, including cyclin A and CDK1, thus enhancing DNA synthesis to copy with DNA damage. In head and neck squamous cell carcinoma, mutant p53 participates in transcriptional regulation of its target genes including MYC, SMARCD1 and AMPK to promote cell proliferation by binding to their DNA domains. By binding to DNA regions, mutant p53 can regulate the expression of particular ncRNAs, including lincRNA-p21, lncMIR205HG, miR-205-5p and circPVT1, leading to apoptosis, proliferation and DNA damage repair. p53 regulates the upregulation of the IL17 signaling pathway in the tumor microenvironment and depletes CD8+ cells, thus abolishing the immunotherapeutic effect of anti-PD-1 antibody treatment in OSCC. Mutant p53 exerts GOF activity by interacting with p63 and p73 to inhibit the expression of related proteins, including PUMA/Bax, to inhibit apoptosis. GOF, gain-of-function; TF, transcription factor; NF-Y, nuclear transcription factor Y subunit α; CDK1, cyclin dependent kinase 1; ncRNAs, noncoding RNAs; IL17, interleukin 17; OSCC, oral squamous cell carcinoma; RE, response element; PD-1, programmed cell death protein-1; AMPK, adenosine monophosphate-activated protein kinase; Bax, Bcl-2-associated X; PUMA, p21/p53 upregulated modulator of apoptosis

Publication

Mutant p53 in head and neck squamous cell carcinoma: Molecular mechanism of gain‑of‑function and targeting therapy (Review) (2023) Minmin Li, et al. Oncol Rep. 2023 Sep;50(3). Figure: F2. Homo sapiens

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