MicroRNAs as Key Effectors in the p53 Network

Goeman, Frauke; Strano, Sabrina; Blandino, Giovanni

doi:10.1016/bs.ircmb.2017.04.003

Cited by 41 publications

(34 citation statements)

References 180 publications

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“…miRNAs can also bind coding regions, 5 -UTR, and open reading frames (ORF) regulating in this way the protein translation. Genes encoding miRNAs are transcribed by RNA polymerase II (Pol II) and processed from the nucleus to the cytoplasm through an evolutionarily-conserved pathway [40,41]. To date, over 2000 miRNAs have been discovered in humans and they collectively may regulate one third of the mRNAs [40][41][42].…”

Section: Mutant P53 and Mirnasmentioning

confidence: 99%

“…MicroRNAs have been linked to many human diseases and are potentially important targets for the diagnostics and therapy. Due to the imperfect complementarity needed for binding target mRNAs, miRNAs have the potential to target hundreds of mRNAs that can fit both tumor suppression and oncogenesis-gene expression, protein regulation, homeostasis, and diseases [40][41][42].…”

Section: Mutant P53 and Mirnasmentioning

confidence: 99%

“…Wild-type p53 (wt-p53), as principal tumor suppressor in the cells, can modulate the expression of many miRNAs [41,43]. Usually, wt-p53 regulates miRNAs to suppress cancerogenesis, on the other hand GOF mut-p53 directly or indirectly modulates microRNAs by conferring oncogenic properties such as chemoresistance and invasion.…”

Section: Mutant P53 and Mirnasmentioning

confidence: 99%

“…Furthermore, the expression of both wt-and mut-p53 is closely regulated by a fine-tuned machinery including miRNAs. miRNAs directly target p53 RNA or other factors in the p53 network so that expression and function of either the wild-type or mutant p53 proteins are down-regulated [41,43].…”

Section: Mutant P53 and Mirnasmentioning

confidence: 99%

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The Impact of Mutant p53 in the Non-Coding RNA World

Agostino

2020

Biomolecules

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Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other.Biomolecules 2020, 10, 472 2 of 15 heterotetrameric mut-p53/wt-p53 complex can inhibit the function of the remaining wt-p53 in tumor suppression [8,9]. Most of the missense mutations occur in the p53 DNA-binding region and can be classified as either contact mutations (as p53R248 and p53R273 interfere directly with DNA binding) or conformational mutations (as p53R175 induces local or global conformational distortions) [5,9].Six hotspot mutations are the most represented in the cancers. These include R175, G245, R248, R249, R273, and R282, which make up about 30% of all mutations in TP53 covering all human cancer types [8][9][10]. However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered. mut-p53 GOF has been demonstrated by numerous cell-based experiments such as by ectopic expression of mut-p53 proteins in p53-null human tumor cells or knockdown of endogenous mut-p53 in cells containing only one allele of mutant p53, as well as in mutant p53 knock-in mouse models [5,[8][9][10]. Genome sequencencing has highlighted that more than 91% of TP53-mutant cancers exhibit loss of the second allele (LOH) by mutation or DNA deletion [11].Many mut-p53 GOF activities have been identified as tumor cell proliferation, survival, migration and invasion, enhancing chemoresistance, disrupting proper tissue architecture, inducing cancer metabolism (Warburg effect and lipid metabolism), and increasing genomic instability and mitochondrial dysfunction [5,[10][11][12][13][14][15] (Figure 1).

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Section: Mutant P53 and Mirnasmentioning

confidence: 99%

Section: Mutant P53 and Mirnasmentioning

confidence: 99%

Section: Mutant P53 and Mirnasmentioning

confidence: 99%

Section: Mutant P53 and Mirnasmentioning

confidence: 99%

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The Impact of Mutant p53 in the Non-Coding RNA World

Agostino

2020

Biomolecules

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“…This dysregulation is intertwined with the genetic alterations affecting one of the most important tumour suppressive pathways, the p53 pathway. Indeed, the tumour suppressor p53 is the main cellular hub responsible for maintaining cellular homoeostasis and genome integrity, and it fulfils its roles by controlling the expression of protein-coding and non-coding genes alike [16][17][18]. Given its centrality in counteracting stimuli that can perturb the physiological conditions of cells [19,20], the loss of p53 functions is a common feature of human cancers [21], and numerous animal models have shown that either lack [22,23] of or mutations [24,25] in the TP53 gene determines the onset of a variety of tumours and can recapitulate the human tumour-predisposing syndrome, known as Li-Fraumeni. Despite being considered unique to the point of deserving the title of the 'guardian of the genome' [26], it is now clear that p53 is supported in its activities by the other members of its family, p63 and p73 [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

Napoli

Flores

2020

RNA Biology

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The tumour suppressor p53 and its paralogues, p63 and p73, are essential to maintain cellular homoeostasis and the integrity of the cell's genetic material, thus meriting the title of 'guardians of the genome'. The p53 family members are transcription factors and fulfill their activities by controlling the expression of protein-coding and non-coding genes. Here, we review how the latter group transcended from the 'dark matter' of the transcriptome, providing unexpected and intriguing anti-cancer therapeutic strategies. ARTICLE HISTORY

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LncRNA CARMN m6A demethylation by ALKBH5 inhibits mutant p53‐driven tumour progression through miR‐5683/FGF2

Liu,

Jiang,

Zhang

et al. 2024

Clinical & Translational Med

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N‐methyladenosine (m6A) represents a prevalent RNA modification observed in colorectal cancer. Despite its abundance, the biological implications of m6A methylation on the lncRNA CARMN remain elusive in colorectal cancer, especially for mutant p53 gain‐of‐function. Here, we elucidate that CARMN exhibits diminished expression levels in colorectal cancer patients with mutant p53, attributed to its rich m6A methylation, which promotes cancer proliferation, invasion and metastasis in vitro and in vivo. Further investigation illustrates that ALKBH5 acts as a direct demethylase of CARMN, targeting 477 methylation sites, thereby preserving CARMN expression. However, the interaction of mutant p53 with the ALKBH5 promoter impedes its transcription, enhancing m6A methylation levels on CARMN. Subsequently, YTHDF2/YTHDF3 recognise and degrade m6A‐modified CARMN. Concurrently, overexpressing CARMN significantly suppressed colorectal cancer progression in vitro and in vivo. Additionally, miR‐5683 was identified as a direct downstream target of lncRNA CARMN, exerting an antitumour effect by cooperatively downregulating FGF2 expression. Our findings revealed the regulator and functional mechanism of CARMN in colorectal cancer with mutant p53, potentially offering insights into demethylation‐based strategies for cancer diagnosis and therapy. The m6A methylation of CARMN that is prime for mutant p53 gain‐of‐function‐induced malignant progression of colorectal cancer, identifying a promising approach for cancer therapy.

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MicroRNAs as Key Effectors in the p53 Network

Cited by 41 publications

References 180 publications

The Impact of Mutant p53 in the Non-Coding RNA World

The Impact of Mutant p53 in the Non-Coding RNA World

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

LncRNA CARMN m6A demethylation by ALKBH5 inhibits mutant p53‐driven tumour progression through miR‐5683/FGF2

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