Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

Abstract

Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling‐targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor‐promoting role by blocking the mitochondria‐dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.

In Silico and In Vitro Exploration of Poziotinib and Olmutinib Synergy in Lung Cancer: Role of hsa-miR-7-5p in Regulating Apoptotic Pathway Marker Genes

“…When TRIAP1 is overexpressed, it can impede the activation of APAF1/apoptosome, consequently blocking apoptosis in cancer cells. This inhibition of programmed cell death contributes to the advancement of cancer and its progression [48,49]. Future studies should confirm the downregulation of miR-5-7p and hence of TRIAP1 in the synergism of poziotinib and olmutinib.…”

Hawthorn with “homology of medicine and food”: a review of anticancer effects and mechanisms

“…p53, a well-researched suppressor of tumor growth, plays a crucial role in initiating various biological responses. Its abnormal activation has a strong connection to the onset and progression of cancer ( Huang, 2021 ; Shen et al, 2023 ). Yang et al (2013) observed an upregulation of p53 expression and its downstream genes, p21 WAF1 and Bax, upon exposure of oral cancer cells to vitexin.…”

The p53 tumor suppressor protein activates transcription of DUSP13 isoform from the alternative promoter in intron

“…The early-identified p53-regulated genes coded for proteins promoting apoptosis, cell cycle arrest and DNA repair. However, as many more genes directly activated by p53 have been discovered, it was realized that p53 regulates wide spectrum of biological functions including metabolism, aging, angiogenesis, immunity, and more [1][2][3]. The p53 binds as a tetramer to its response element (RE) RRRCWWGYYYRRRCWWGYYY (R -A or G, Y -C or T, W -A or T) consisting of two decameric half sites divided further into four pentameric quarter sites (RRRCW or WGYYY).…”

“…This arrangement allows for some flexibility in the selection of p53 binding sites, which sometime can deviate from the consensus sequence [4]. 2 Recently, we published the transcriptomic data showing changes in gene expression in A549 lung cancer cell line exposed to actinomycin D and nutlin-3a (henceforth abbreviated to A+N) [5]. Earlier, we noticed that these two substances synergize in activation of p53 and in activation of some p53-regulated genes [6,7].…”