The p53 protein induces stable miRNAs that have the potential to modify subsequent p53 responses

Cabrita, Miguel A.; Bose, Reetesh; Vanzyl, Erin J.; Pastic, Alyssa; Marcellus, Kristen A.; Pan, Elysia; Hamill, Jeff D.; McKay, Bruce C.

doi:10.1016/j.gene.2017.01.018

Cited by 12 publications

(16 citation statements)

References 51 publications

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“…Although these miRNAs appear to follow a similar pattern to mRNAs, there were no statistically significant changes in expression levels over the 48hr treatment ( Figure 11B). This did not indicate a clear p53 response from target miRNAs, different from the significant changes observed in our previous temperature sensitive model (Cabrita et al, 2017).…”

Section: Absence Of Mirna Feedback In Response To Long Term Nutlin-3acontrasting

confidence: 99%

“…were not induced as strongly during the second response (Cabrita et al, 2017). The affected transcripts were predicted targets of p53-regulated miRNAs (miR-34A, miR-143 and miR-145).…”

Section: Rationalementioning

confidence: 93%

“…When cells were returned to the restrictive temperature, mRNAs decayed rapidly returning to basal levels within hours, while the co-expressed miRNAs were stably expressed, remaining elevated for days in the absence of functional p53 (Cabrita et al, 2017). The difference in stability of these classes of p53-regulated RNAs led to high miRNA but low p53-regulated mRNA levels following recovery.…”

Section: Rationalementioning

confidence: 99%

“…Therefore, cells were placed at the permissive temperature, returned to the restrictive temperature and again incubated at the permissive temperature to activate p53 a second time (Cabrita et al, 2017). Under these conditions, a subset of p53-induced mRNAs including MDM2…”

Section: Rationalementioning

confidence: 99%

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The Role of miRNAs and Alternative Polyadenylation in Modulating the P53 Response

Browning¹

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The p53 protein is an important tumor-suppressor that is negatively regulated by MDM2, itself a p53-induced protein. Here we used nutlin-3A, a reversible inhibitor of MDM2, to activate the p53 response in HCT116 cells and isogenic miRNA-processing defective Drosha and Dicer knockout sublines, to determine the role of miRNAs in this feedback loop. We provide evidence that miRNAs inhibit MDM2 mRNA and protein levels when cells are exposed to nutlin-3A twice, separated by a period of recovery. Surprisingly, MDM2 transcripts with the longest 3'UTRs escaped miRNA-mediated repression, while specific isoforms with shorter 3'UTRs were attenuated in parental cells and over-expressed in the miRNA processing defective knockouts. We propose that miRNA recognition sites are placed in a more accessible context within these shorter 3'UTR variants. Thus, polyadenylation site selection represents a novel regulatory mechanism in the p53 response, with the potential to impact the p53-MDM2 feedback loop and p53-mediated tumor suppression.

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Section: Absence Of Mirna Feedback In Response To Long Term Nutlin-3acontrasting

confidence: 99%

“…were not induced as strongly during the second response (Cabrita et al, 2017). The affected transcripts were predicted targets of p53-regulated miRNAs (miR-34A, miR-143 and miR-145).…”

Section: Rationalementioning

confidence: 93%

Section: Rationalementioning

confidence: 99%

Section: Rationalementioning

confidence: 99%

See 2 more Smart Citations

The Role of miRNAs and Alternative Polyadenylation in Modulating the P53 Response

Browning¹

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“…It has been shown that miRNAs are involved in the regulation of malignant tumorigenesis and the proliferation, invasion and migration of tumor cells. MicroRNA-145 (miR-145), an important member of miRNA, has been shown to be down-regulated in many tumor tissues, such as cervical cancer, ovarian cancer, and endometrial cancer [1][2][3] . It is suggested that miR-145 may act as a tumor suppressor gene and regulate tumorigenesis and development [4] .…”

Section: Introductionmentioning

confidence: 99%

Microrna -145 Expression Inhibits Invasion and Metastasis of Cervical Cancer Cells

Zhou¹,

Liu²,

Lin³

2017

Proceedings of the 2nd International Conference on Biomedical and Biological Engineering 2017 (BBE 2017)

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Abstract. [Purposes] To investigate the expression of microRNA-145 on invasion and metastasis of cervical cancer cells.[Methods] Analysis of the relationship between high expression of microRNA-145 on invasion and metastasis of cervical cancer cells by Transwell invasion assay and Wound scratch assay. [Results] There is a certain correlation between inhibit the invasion and metastasis and microRNA-145 high expression in cervical cancer cells (P<0.05).[Conclusions] MicroRNA-145 inhibiting cervical cancer invasion and metastasis in the occurrence and development of cervical cancer. Can be used for targeted therapy of cervical cancer and prognosis judgement index.

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TGF-β1/p53 signaling in renal fibrogenesis

Higgins

Tang

Higgins

et al. 2018

Cellular Signalling

125

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Fibrotic disorders of the renal, pulmonary, cardiac, and hepatic systems are associated with significant morbidity and mortality. Effective therapies to prevent or curtail the advancement to organ failure, however, remain a major clinical challenge. Chronic kidney disease, in particular, constitutes an increasing medical burden affecting >15% of the US population. Regardless of etiology (diabetes, hypertension, ischemia, acute injury, urologic obstruction), persistently elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling networks and disease progression. TGF-β1 is the principal driver of renal fibrogenesis, a dynamic pathophysiologic process that involves tubular cell injury/apoptosis, infiltration of inflammatory cells, interstitial fibroblast activation and excess extracellular matrix synthesis/deposition leading to impaired kidney function and, eventually, to chronic and end-stage disease. TGF-β1 activates the ALK5 type I receptor (which phosphorylates SMAD2/3) as well as non-canonical (e.g., src kinase, EGFR, JAK/STAT, p53) pathways that collectively drive the fibrotic genomic program. Such multiplexed signal integration has pathophysiological consequences. Indeed, TGF-β1 stimulates the activation and assembly of p53-SMAD3 complexes required for transcription of the renal fibrotic genes plasminogen activator inhibitor-1, connective tissue growth factor and TGF-β1. Tubular-specific ablation of p53 in mice or pifithrin-α-mediated inactivation of p53 prevents epithelial G/M arrest, reduces the secretion of fibrotic effectors and attenuates the transition from acute to chronic renal injury, further supporting the involvement of p53 in disease progression. This review focuses on the pathophysiology of TGF-β1-initiated renal fibrogenesis and the role of p53 as a regulator of profibrotic gene expression.

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The p53 protein induces stable miRNAs that have the potential to modify subsequent p53 responses

Cited by 12 publications

References 51 publications

The Role of miRNAs and Alternative Polyadenylation in Modulating the P53 Response

The Role of miRNAs and Alternative Polyadenylation in Modulating the P53 Response

Microrna -145 Expression Inhibits Invasion and Metastasis of Cervical Cancer Cells

TGF-β1/p53 signaling in renal fibrogenesis

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