The “LINC” in between Δ40p53-miRNA axis in the regulation of cellular homeostasis

Pal, Apala

doi:10.1101/2022.04.28.489891

Cited by 2 publications

(2 citation statements)

References 78 publications

(166 reference statements)

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“…We found that Δ40p53 (and not FLp53) uniquely regulates miR-186-5p, which can downregulate expression of the known oncogene Ying Yang 1 (YY1) protein, thereby decreasing cell proliferation 22 . In another study we have also found that Δ40p53 regulates lncRNA (LINC00176) which can control cell fate mediated through multiple miRNA and mRNAs 23 . Contrary to its tumor suppressive role Δ40p53 independently activates the netrin-1 promoter and promotes cell survival 24 .…”

Section: Introductionmentioning

confidence: 81%

p53 translational-isoform Δ40p53 regulates cell cycle by modulating the miR-4671-5p/SGSH axis

Pal

Khan

Tripathi

et al. 2023

Preprint

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The translational isoform of full-length p53, Δ40p53, modulates the p53 pathway. We previously showed that Δ40p53 regulates miR-186-5p-YY1 axis, independent of p53, to decrease cell proliferation. In this study, we screened small RNA sequences globally to identify miRNAs differentially regulated by Δ40p53 and p53. We report that the expression of certain miRNAs is exclusively regulated by Δ40p53. Overexpression of Δ40p53, but not full-length p53, substantially downregulated expression of the novel miR-4671-5p. However, upon over expression of different ratios of Δ40p53 and FLp53, miR-4671-5p levels changed which implies that this novel miRNA is not a direct but a p53 modifiable target. Predicted miR-4671-5p targets included N-sulfoglucosamine sulfohydrolase (SGSH), cyclin-dependent kinases (CDK) 11B and CDK5 regulatory subunit 1 (CDK5R1). Overexpression of miR-4671-5p directly inhibited SGSH and consequently triggered intra-S-phase cell cycle arrest. Δ40p53-miR-4671-5p-SGSH axis emerges as a novel axis capable of regulating cell cycle progression. SGSH gene expression levels have potential prognostic relevance on survival that trends in the opposite direction of miR-4671-5p levels associated with the same cancer types, supporting a possible physiological relevance of the interaction. These results enhance understanding of Δ40p53 functions mediated by miRNAs that help to maintain metabolic and cellular homeostasis independently of FLp53.

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Section: Introductionmentioning

confidence: 81%

p53 translational-isoform Δ40p53 regulates cell cycle by modulating the miR-4671-5p/SGSH axis

Pal

Khan

Tripathi

et al. 2023

Preprint

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“…It has been shown that the p53 isoforms contribute to the regulation of the p53 pathway by regulating the expression of p53 target genes 9,10,11 . Notably, p53 isoforms exhibit both overlapping and distinct functions compared to the canonical p53 11,12,13 and have been reported to promote tumor progression in various cancers 11,14 . The p53 isoforms are generated through alternative promoter usage, alternative splicing, and alternative transcription starting site usage 9,15 .…”

Section: Introductionmentioning

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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The “LINC” in between Δ40p53-miRNA axis in the regulation of cellular homeostasis

Cited by 2 publications

References 78 publications

p53 translational-isoform Δ40p53 regulates cell cycle by modulating the miR-4671-5p/SGSH axis

p53 translational-isoform Δ40p53 regulates cell cycle by modulating the miR-4671-5p/SGSH axis

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

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