Applications of p53 Knockout Cell Lines in Understanding Tumor Suppression and Beyond

The tumor suppressor gene p53 is the most frequently mutated gene during tumorigenesis, and mutations in the p53 gene have been detected in more than 50% of human tumors. p53 protein is activated under conditions of cellular stress, such as DNA damage, and regulates a variety of cellular processes, including cell cycle blockade, inhibition of cell proliferation, and promotion of apoptosis. The use of knockout cell lines has revolutionized cancer research by providing a powerful tool to study the functions and regulatory mechanisms of p53. This resource article explores the diverse applications of p53 knockout cell lines, shedding light on their significance and impact in cancer research and beyond.

p53 Signaling Pathways

The transcription factor p53 plays a central part in the cell cycle and is arguably the most important tumor suppressor. Upon cellular stress signals, such as DNA damage or oncogenic stress, p53 is activated through a cascade of phosphorylation events and other posttranslational modifications (PTMs), resulting in the expression of p53 target genes involved in cell-cycle arrest, DNA repair, or apoptosis, if the damage is irreparable. The p53 target genes also have important roles in senescence, angiogenesis, and autophagy, connecting, for example, p53 and mammalian target of rapamycin (mTOR) signaling. Over the years, countless studies on p53 have increasingly revealed the complexity and connectivity of the p53 pathway, which extends to roles in metabolic regulation, development, and stem cell biology.

Fig. 1 The p53 pathway.

Unveiling p53 Mutations and Oncogenic Processes

In 50% or more of human cancer types, p53 is directly inactivated by mutation. The prevalence of p53 mutation varies significantly by cancer type and also depends on the developmental stage of a tumor, with prevalences ranging from less than 5% in cervical cancer and 10% in leukemia to 80% in small-cell lung cancer and 90% in ovarian cancer. Most cancer-associated mutations are located in the DBD, and there are several mutational hotspots within the DBD, with the most frequent somatic cancer mutations being R175H, Y220C, G245S, R248Q/W, R249S, R273C/H, and R282W. Cancer mutations in the intrinsically disordered regions of p53 are relatively rare. Mutations in the tetramerization domain are a special case. They have a low frequency among somatic mutations, but a mutation in the tetramerization domain, R337H, is the most frequent p53 germ-line mutation currently known. This mutation predisposes to multiple cancers, but has a relatively low penetrance below the age of 30.

Fig. 2 p53 cancer mutations.

Application of p53 Knockout Cell Lines

p53 knockout cell lines have significantly advanced our understanding of the complex functions and regulatory mechanisms of p53 in cancer and various other fields of research. By utilizing these cell lines, researchers can unravel the mysteries surrounding p53, unravel its intricate signaling pathways, investigate its role in oncogenic processes, explore therapeutic strategies, and delve into its broader implications in stem cell biology, aging, and developmental biology.

The expanding use of our ready-to-use p53 knockout cell lines is paving the way for new discoveries and potential therapeutic interventions in cancer and beyond.

Cat.No.	Product Name	Price
CSC-DC016452	Panoply™ Human TP53 Knockdown Stable Cell Line	Inquiry
CSC-RK0023	Human p53 Knockdown Cell Line-HeLa	Inquiry
CSC-RT0009	Human TP53 Knockout Cell Line-DLD1	Inquiry
CSC-RT0014	Human TP53 Knockout Cell Line-SW48	Inquiry
CSC-RT0033	Human TP53 Knockout Cell Line-MCF10A	Inquiry
CSC-RT0041	Human TP53 (+/-) Knockout Cell Line-HCT116	Inquiry
CSC-RT0046	Human TP53 (-/-) Knockout Cell Line-HCT116	Inquiry
CSC-RT0109	TP53 Knockout Cell Line-HepG2	Inquiry
CSC-RT0369	TP53 Knockout Cell Line-293T	Inquiry
CSC-RT0495	TP53 Knockout Cell Line-HeLa	Inquiry
CSC-RT2704	Human TP53 Knockout Cell Line-MV-4-11	Inquiry
CSC-RT2760	Human TP53 Knockout Cell Line-MOLM13	Inquiry
CSC-SC016452	Panoply™ Human TP53 Over-expressing Stable Cell Line	Inquiry

Unraveling the mechanism of p53 interactions with BCL-2

p53 and the B-cell lymphoma-2 (BCL-2) family of proteins play crucial roles in mediating apoptosis. p53 can act as a transcription factor to regulate the expression of apoptosis-related genes as well as a transcription-independent regulator of mitochondrial apoptosis through direct interactions with the BCL-2 family of proteins, yet little is known about the molecular mechanisms of the interactions between p53 and the BCL-2 family of proteins. However, little is known about the molecular mechanism of the interaction between p53 and BCL-2 family proteins.

Using the constructed HCT116 cell line with knockdown of TP53 gene, a new mechanism of p53 interacting with BCL-2 protein and promoting apoptosis was revealed by resolving the crystal structure of the complex of p53 with the anti-apoptotic protein BCL-2 and combining with biochemical and cellular experiments. Namely, p53 promotes apoptosis by directly occupying the BH3-binding pocket of BCL-2 to form a complex with it and antagonizing BCL-2 activity by releasing pro-apoptotic BCL-2 family proteins located in the pocket. These structural and functional data provide new ideas to further understand the complex regulatory mechanisms of p53-mediated mitochondrial apoptosis, and provide an important basis for the development of anticancer therapeutic strategies that target protein-protein interactions to activate apoptosis.

References:

Joerger, A. C.; et al. The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annual review of biochemistry. 2016, 85: 375-404.
Wei, H.; et al. Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity. Nature Communications. 2023, 14(1): 4300.

* For research use only. Not intended for any clinical use.

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Applications of p53 Knockout Cell Lines in Understanding Tumor Suppression and Beyond

p53 Signaling Pathways

Unveiling p53 Mutations and Oncogenic Processes

Application of p53 Knockout Cell Lines

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