Interplay between PTB and miR-1285 at the p53 3′UTR modulates the levels of p53 and its isoform Δ40p53α

Katoch, Aanchal; George, Biju; Iyyappan, Amrutha; Khan, Debjit

doi:10.1093/nar/gkx630

Cited by 14 publications

(11 citation statements)

References 24 publications

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“…A prior study had proposed an interplay between cis-regulatory elements in the TP53 3′UTR and usage of a downstream start codon resulting in a p53 protein isoform lacking one of the Nterminal transactivation domains (Katoch et al, 2017). Importantly, the region that has been implicated in this process is deleted in our TP53 dUTR allele.…”

Section: Resultsmentioning

confidence: 92%

Endogenous p53 expression in human and mouse is not regulated by its 3′UTR

Mitschka

Mayr

2021

eLife

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The TP53 gene encodes the tumor suppressor p53 which is functionally inactivated in many human cancers. Numerous studies suggested that 3′UTR-mediated p53 expression regulation plays a role in tumorigenesis and could be exploited for therapeutic purposes. However, these studies did not investigate post-transcriptional regulation of the native TP53 gene. Here, we used CRISPR/Cas9 to delete the human and mouse TP53/Trp53 3′UTRs while preserving endogenous mRNA processing. This revealed that the endogenous 3′UTR is not involved in regulating p53 mRNA or protein expression neither in steady state nor after genotoxic stress. Using reporter assays, we confirmed the previously observed repressive effects of the isolated 3′UTR. However, addition of the TP53 coding region to the reporter had a dominant negative impact on expression as its repressive effect was stronger and abrogated the contribution of the 3′UTR. Our data highlight the importance of genetic models in the validation of post-transcriptional gene regulatory effects.

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Section: Resultsmentioning

confidence: 92%

Endogenous p53 expression in human and mouse is not regulated by its 3′UTR

Mitschka

Mayr

2021

eLife

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“…A knockdown of miR-1285, enhance the association of PTB with the 3′UTR. The interplay between miR-1285, p53 3′UTR and PTB play a pivotal role in the expression of both isoforms of p53 (59). Some other regulatory RNAs (long non-coding RNAs) also impact p53 translation via direct or indirect interactions (for review see (60)).…”

Section: Introductionmentioning

confidence: 99%

The p53 mRNA: an integral part of the cellular stress response

Hároníková

Olivares‐Illana

Wang

et al. 2019

Nucleic Acids Research

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A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs.

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“…To date, only a few reports have described the role of miR-1285-3p in cancer, showing that it can act as both tumor-suppressor and onco-miR, depending on the context and tumor type [29][30][31]. This apparent controversial, dual role of microRNAs has been already reported as a consequence of differential gene expression patterns, determining a tumor-specific interactome for a given microRNA.…”

Section: Discussionmentioning

confidence: 99%

miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2

Villanova

Barbini

Piccolo

et al. 2020

IJMS

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MicroRNAs are tiny but powerful regulators of gene expression at the post-transcriptional level. Aberrant expression of oncogenic and tumor-suppressor microRNAs has been recognized as a common feature of human cancers. Colorectal cancer represents a major clinical challenge in the developed world and the design of innovative therapeutic approaches relies on the identification of novel biological targets. Here, we perform a functional screening in colorectal cancer cells using a library of locked nucleic acid (LNA)-modified anti-miRs in order to unveil putative oncogenic microRNAs whose inhibition yields a cytotoxic effect. We identify miR-1285-3p and further explore the effect of its targeting in both commercial cell lines and primary colorectal cancer stem cells, finding induction of cell cycle arrest and apoptosis. We show that DAPK2, a known tumor-suppressor, is a novel miR-1285 target and mediates both the anti-proliferative and the pro-apoptotic effects of miR-1285 depletion. Altogether, our findings uncover a novel oncogenic microRNA in colorectal cancer and lay the foundation for further studies aiming at the development of possible therapeutic strategies based on miR-1285 targeting.

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Interplay between PTB and miR-1285 at the p53 3′UTR modulates the levels of p53 and its isoform Δ40p53α

Cited by 14 publications

References 24 publications

Endogenous p53 expression in human and mouse is not regulated by its 3′UTR

Endogenous p53 expression in human and mouse is not regulated by its 3′UTR

The p53 mRNA: an integral part of the cellular stress response

miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2

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