The p53 Pathway Encounters the MicroRNA World

Takwi, Apana; Li, Yong

doi:10.2174/138920209788185270

Cited by 31 publications

(23 citation statements)

References 36 publications

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“…The substitution of mutant p53 and inhibition of Ras-induced senescence are functions of miR-371-373 up-regulation in TGCTs [70]. Patients with p53-positive TGCTs and upregulated miR-371-373 are less resistant to chemotherapy and radiation treatment [70][71][72][73].…”

Section: Mir-371-373 Clustermentioning

confidence: 99%

Non-Coding microRNAs as Novel Potential Tumor Markers in Testicular Cancer

Regouc

Belge

Lorch

et al. 2020

Cancers

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Testicular cancer is an important disease with increasing incidence and a high burden of morbidity and mortality in young men worldwide. Histological examination of the testicular tissue after orchiectomy plays an important role alongside patient history, imaging, clinical presentation and laboratory parameters. Surgical procedures and chemotherapeutic treatment provide a high chance of cure in early stages, though some patients in advanced stages belonging to a poor risk group experience cancer-related death. Though conventional serum-based tumor markers, including α-fetoprotein (AFP), the β-subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), are useful as prognostic and diagnostic biomarkers, unfortunately, these tumor markers only have a sensitivity of about 60%, and in pure seminoma even lower with about 20%. Therefore, the development of new tumor markers is an important and intensively ongoing issue. The analysis of epigenetic modification and non-coding RNA microRNAs (miRNAs) are carrying most promising potential as tumor markers in future. miRNAs are small RNAs secreted by testicular tumor cells and circulate and be measurable in body fluids. In recent years, miRNAs of the miR-371-373 cluster in particular have been identified as potentially superior tumor markers in testicular cancer patients. Studies showed that miR-371a-3p and miR-302/367 expression significantly differ between testicular tumors and healthy testicular tissue. Several studies including high prospective multi-center trials clearly demonstrated that these miRNAs significantly exceed the sensitivity and specificity of conventional tumor markers and may help to facilitate the diagnosis, follow-up, and early detection of recurrences in testicular cancer patients. In addition, other miRNAs such as miR-223-3p, miR-449, miR-383, miR-514a-3p, miR-199a-3p, and miR-214 will be discussed in this review. However, further studies are needed to identify the value of these novel markers in additional clinical scenarios, including the monitoring in active surveillance or after adjuvant chemotherapy, but also to show the limitations of these tumor markers. The aim of this review is to give an overview on the current knowledge regarding the relevance of non-coding miRNAs as biomarkers in testicular cancer.

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Section: Mir-371-373 Clustermentioning

confidence: 99%

Non-Coding microRNAs as Novel Potential Tumor Markers in Testicular Cancer

Regouc

Belge

Lorch

et al. 2020

Cancers

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“…Activation of p53 affects the expression level of a large set of genes and mediates several cellular responses such as DNA repair, cell cycle arrest and/or apoptosis (Vogelstein et al, 2000;Levine et al, 2006). Although it is well established that p53 is a transcriptional regulator, transactivation-independent functions of p53 have been described (reviewed by He et al, 2007;Takwi and Li, 2009). For example, certain microRNAs are transactivated by p53, and these microRNAs cause dramatic changes in gene expression, offering an indirect p53-mediated control of gene expression at the posttranscriptional level (Chang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

et al. 2011

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The mechanisms involved in the p53-dependent control of gene expression following DNA damage have not been completely elucidated. Here, we show that the p53 C terminus associates with factors that are required for the ultraviolet (UV)-induced inhibition of the mRNA 3 0 cleavage step of the polyadenylation reaction, such as the tumor suppressor BARD1 and the 3 0 processing factor cleavage-stimulation factor 1 (CstF1). We found that p53 can coexist in complexes with CstF and BARD1 in extracts of UV-treated cells, suggesting a role for p53 in mRNA 3 0 cleavage following DNA damage. Consistent with this, we found that p53 inhibits 3 0 cleavage in vitro and that there is a reverse correlation between the levels of p53 expression and the levels of mRNA 3 0 cleavage under different cellular conditions. Supporting these results, a tumor-associated mutation in p53 not only decreases the interaction with BARD1 and CstF, but also decreases the UV-induced inhibition of 3 0 processing, all of which is restored by wild-type-p53 expression. We also found that p53 expression levels affect the polyadenylation levels of housekeeping genes, but not of p21 and c-fos genes, which are involved in the DNA damage response (DDR). Here, we identify a novel 3 0 RNA processing inhibitory function of p53, adding a new level of complexity to the DDR by linking RNA processing to the p53 network.

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“…This occurs via specific DNA binding of the p53 protein to a p53 response element that is found either in promoters or introns of target genes (1). Transactivation-independent functions of p53 have also been described (2). For example, certain microRNAs (miRNAs) are regulated by p53, and these miRNAs cause dramatic changes in gene expression, offering an indirect p53-mediated control of gene expression at the posttranscriptional level (3).…”

mentioning

confidence: 99%

Positive and negative feedback loops in the p53 and mRNA 3′ processing pathways

Devany

Zhang

Park

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

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Although the p53 network has been intensively studied, genetic analyses long hinted at the existence of components that remained elusive. Recent studies have shown regulation of p53 at the mRNA level mediated via both the 5′ and the 3′ untranslated regions and affecting the stability and translation efficiency of the p53 mRNA. Here, we provide evidence of a feedback loop between p53 and the poly(A)-specific ribonuclease (PARN), in which PARN deadenylase keeps p53 levels low in nonstress conditions by destabilizing p53 mRNA, and the UV-induced increase in p53 activates PARN deadenylase, regulating gene expression during DNA damage response in a transactivation-independent manner. This model is innovative because it provides insights into p53 function and the mechanisms behind the regulation of mRNA 3′ end processing in different cellular conditions. deadenylation | mRNA 3′ processing | mRNA steady state levels | gene expression control D ownstream signaling in the p53 pathway includes several cellular responses. The expression of a large number of genes involved in DNA repair, cell cycle arrest, and/or apoptosis is regulated by transactivating properties of p53. This occurs via specific DNA binding of the p53 protein to a p53 response element that is found either in promoters or introns of target genes (1). Transactivation-independent functions of p53 have also been described (2). For example, certain microRNAs (miRNAs) are regulated by p53, and these miRNAs cause dramatic changes in gene expression, offering an indirect p53-mediated control of gene expression at the posttranscriptional level (3). Recently, we showed that p53 can inhibit mRNA 3′ cleavage through its interaction with the cleavage stimulation factor 1 (CstF1) (4). CstF1 can also interact with poly(A)-specific ribonuclease (PARN) deadenylase, and the CstF1/PARN complex formation has a role in the regulation of gene expression by inhibition of mRNA 3′ cleavage and activation of deadenylation upon DNA damage (5). PARN, an mRNA decay enzyme, has been studied extensively in vitro at the biochemical levels but very little is known of its biological targets and its role in different cellular conditions. Recently, it has been shown that PARN regulates the expression of genes involved in mRNA metabolism, transcription, and cell motility in mouse myoblasts (6). Our studies indicate that the CstF/PARN complex can decrease the mRNA levels of housekeeping genes under DNA-damaging conditions and of genes involved in cell growth and differentiation under nonstress conditions (5).Almost all eukaryotic mRNA precursors, with the exception of histones, undergo a cotranscriptional cleavage followed by polyadenylation at the 3′ end. This first round of polyadenylation is considered a default modification for most mRNAs and confers stability. In contrast, activation of deadenylation alters the length of poly(A) tails, affecting mRNA stability, transport, or translation initiation, and hence gene expression (7). Thus, mechanisms controlling deadenylation are highly regul...

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The p53 Pathway Encounters the MicroRNA World

Cited by 31 publications

References 36 publications

Non-Coding microRNAs as Novel Potential Tumor Markers in Testicular Cancer

Non-Coding microRNAs as Novel Potential Tumor Markers in Testicular Cancer

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

Positive and negative feedback loops in the p53 and mRNA 3′ processing pathways

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