Δ113p53/Δ133p53 converts P53 from a repressor to a promoter of DNA double-stand break repair

Gong, Lu; Chen, Jun

doi:10.1080/23723556.2015.1033587

Cited by 7 publications

(5 citation statements)

References 10 publications

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“…Besides, S100A4 participated in the regulation of Cisplatin-resistance of different cancer cells in a p53-dependent manner [27,28]. Since Cisplatin promoted cancer cell death and inhibited cell viability by inducing DNA double-strand break (DSB) [29,30], and p53 was the hub gene of DSB-induced cell death [31], it was reasonable to hypothesize that S100A4/p53 axis was crucial for regulating Cisplatinresistance of CC cells. Interestingly, previous study found that miR-149-3p inhibited bladder cancer cell proliferation and migration by downregulating S100A4 expression levels [15], which indicated that S100A4/p53 axis might be regulated by miR-149-3p.…”

Section: Introductionmentioning

confidence: 99%

Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis

Liu

Yang

Zhao

et al. 2019

Aging

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Methyltransferase-like 1 (METTL1) mediated 7-methylguanosine (m7G) is crucial for the regulation of chemoresistance in cancer treatment. However, the role of METTL1 in regulating chemoresistance of colon cancer (CC) cells to cisplatin is still unclear. This study established the cisplatin-resistant CC (CR-CC) cells and found that METTL1 was low-expressed in CR-CC cells compared to their paired cisplatin-sensitive CC (CS-CC) cells. Besides, overexpressed METTL1 enhanced the cytotoxic effects of cisplatin on CR-CC cells. In addition, miR-149-3p was the downstream target of METTL1, which could be positively regulated by METTL1. Further results validated that miR-149-3p was low-expressed in CR-CC cells comparing to the CS-CC cells. In addition, the promoting effects of overexpressed METTL1 on cisplatin induced CR-CC cell death were abrogated by synergistically knocking down miR-149-3p. Furthermore, S100A4/p53 axis was the downstream target of METTL1 and miR-149-3p, and either overexpressed METTL1 or miR-149-3p increased p53 protein levels in CR-CC cells, which were reversed by upregulating S100A4. Similarly, the promoting effects of overexpressed METTL1 on cisplatin-induced CR-CC cell death were abrogated by overexpressing S100A4. Taken together, overexpression of METTL1 sensitized CR-CC cells to cisplatin by modulating miR-149-3p/S100A4/p53 axis.

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Section: Introductionmentioning

confidence: 99%

Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis

Liu

Yang

Zhao

et al. 2019

Aging

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“…The human gene TP53 expresses 12 different p53 isoforms with varied sequences and properties. The p53C is the predominant constituent of the isoforms ⌬133p53␤, ⌬133p53␥, ⌬160p53␤, and ⌬160p53␥ (7), which play significant roles in the regulation of full-length p53 expression (8) and behavior in cancerous and normal cells (9,10). Their relative mRNA expression varies in different tissues and has been correlated to stress response and p53 activation (11).…”

mentioning

confidence: 99%

Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain

Kovachev

Banerjee

Rangel

et al. 2017

Journal of Biological Chemistry

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Inactivation of the tumor suppressor protein p53 by mutagenesis, chemical modification, protein-protein interaction, or aggregation has been associated with different human cancers. Although DNA is the typical substrate of p53, numerous studies have reported p53 interactions with RNA. Here, we have examined the effects of RNA of varied sequence, length, and origin on the mechanism of aggregation of the core domain of p53 (p53C) using light scattering, intrinsic fluorescence, transmission electron microscopy, thioflavin-T binding, seeding, and immunoblot assays. Our results are the first to demonstrate that RNA can modulate the aggregation of p53C and full-length p53. We found bimodal behavior of RNA in p53C aggregation. A low RNA:protein ratio (∼1:50) facilitates the accumulation of large amorphous aggregates of p53C. By contrast, at a high RNA:protein ratio (≥1:8), the amorphous aggregation of p53C is clearly suppressed. Instead, amyloid p53C oligomers are formed that can act as seeds nucleating aggregation of p53C. We propose that structured RNAs prevent p53C aggregation through surface interaction and play a significant role in the regulation of the tumor suppressor protein.

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“…In comparison, the oncogenic role of the Δ160p53 isoform in human cancers is less explored 11 , although links have been established between the expression of Δ160p53 isoform and melanoma cells 30 . The mechanisms of the oncogenic potential of p53 isoforms have attracted increasing attention from researchers 14,59,60,61,62,63 . A theory of the dominant-negative effect has been introduced, but its exact details have remained unknown.…”

Section: Discussionmentioning

confidence: 99%

Δ133p53 and Δ160p53 isoforms of the tumor suppressor protein p53 exert dominant-negative effect primarily by co-aggregation

Zhao,

Punga,

Sanyal

2024

Preprint

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p53 is a tumor suppressor protein with multiple isoforms that have shared or specific functions. However, two of its isoforms, Δ133p53 and Δ160p53, with large N-terminal deletions, can aggressively cause cancer. These isoforms exert a dominant negative effect on full-length p53 (FLp53), although the precise molecular mechanisms are unknown. Here, we investigated the mechanisms of action of Δ133p53 and Δ160p53 isoforms using chromatin immunoprecipitation, luciferase expression, subcellular fractionation, and immunofluorescence assays. Our study elucidates that these DNA-binding deficient p53 isoforms form hetero-tetrameric complexes with FLp53 and disrupt FLp53's DNA binding and transcriptional activities when present in a higher proportion than FLp53 in the tetramer. However, these structurally unstable isoforms promote vigorous protein aggregation involving FLp53, disrupting its structure and sequestering it in the cytoplasmic and nuclear aggregates, thereby limiting its availability to function as a transcription activator protein. Thus, co-aggregation of Δ133p53 and Δ160p53 with FLp53, rather than hetero-tetramerization, is the primary factor contributing to their dominant-negative effect. Modulating the stability and aggregation of p53 isoforms could be a novel strategy for cancer therapy.

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Δ113p53/Δ133p53 converts P53 from a repressor to a promoter of DNA double-stand break repair

Cited by 7 publications

References 10 publications

Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis

Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis

Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain

Δ133p53 and Δ160p53 isoforms of the tumor suppressor protein p53 exert dominant-negative effect primarily by co-aggregation

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