Micrornas mirnas are small noncoding rna transcripts that affect various cellular pathways by serving as regulators of gene expression at the translational and transcriptional level. We also found that transcriptionally inactive p53 mutants interfere with a functional assembly between drosha complex and p68, leading to attenuation of mirna processing activity. Molecular basis for the recognition of primary micrornas by the droshadgcr8 complex. The developmentally regulated rnabinding protein lin28 was recently identified as a selective inhibitor of mirna processing in embryonic stem cells and embryonal carcinoma cells. We expect to gain a greater insight into pri mirna processing by the crystallization of drosha, the only key protein in the biogenesis pathway which lacks detailed structural studies. School of life sciences and bioengineering, southwest jiaotong university. Exosomal micrornas derived from colon cancer cells promote. Various routes of mirna maturation that are tightly regulated by signaling cascades and specific to an individual or a subclass of mirnas have been recently identified. Micromanaging vascular smooth muscle cell differentiation. Mutation of mirna target site competition for mirna binding by cernas 5 modulation of target site accesibilty by rbps rbp loss of mirna target sites by somatic translocation or altenative splicing a b c mrna mrna p68 xpo5 drosha mature mirna downregulation figure 1 e mirna deregulation in cancer. Normal microrna maturation and germline stem cell maintenance requires loquacious, a doublestranded rnabinding domain protein.
Since mirnas are involved in a broad range of developmental and physiological processes their deregulation appears to play a fundamental role in the onset, progression. Frontiers microrna in cardiovascular aging and agerelated. Xu yuan 1, zhang ailing 2, xiao guang 1, zhang zhe 1, chen zanmou 1, zhang hao 1, li jiaqi 1. The role of mir2 in microrna processing german leonova, richard greavesa, jon timmisb, dimitris lagosa university of york. The induction of p53 was marked in kelly and imr32 cells, moderate in shep cells and also occurred in tp53 mutant, sknbe2c cells figure 3a. An important morphological feature of vsmcs migrating in vitro is a membrane structure called a podosome gimona et al. The tumor suppressor protein p53 was recently identified to modulate mirna processing through association with p68 and drosha, similarly to the rsmads. Apr 23, 2018 the ced is essential for drosha processing activity and is composed of a platform and a piwiargonautezwille paz. Recent studies have demonstrated that mirnas interact with p53 and its network at. Modulation of micrornas by phytochemicals in cancer.
Over the last decades, life expectancy has significantly increased although several chronic diseases persist in the population, with aging as the leading risk factor. How is mirna expression regulated in the dna damage response. The expressions of mirna are dysregulated in several human cancers, and functional mirna defects are known to be related to carcinogenesis calin et al. Jul 23, 2009 we also found that transcriptionally inactive p53 mutants interfere with a functional assembly between drosha complex and p68, leading to attenuation of mirna processing activity. Navigating the micronome using multiple microrna prediction databases to identify signalling pathwayassociated micrornas elize a. Regulatory mechanisms of microrna expression journal of. Microrna 145 suppresses cell invasion and metastasis by directly targeting mucin 1. Modulation of microrna processing by p53 pubmed result. Jul 15, 2011 yang w, chendrimada tp, wang q, higuchi m, seeburg ph, shiekhattar r, nishikura k 2006 modulation of microrna processing and expression through rna editing by adar deaminases. Indeed, it was demonstrated that, following dna damage, p53 interacts with drosha processing complex enhancing the posttranscriptional maturation of several tumor suppressor mirnas, namely mir16. Several reports suggest that mir145 can be induced transcriptionally by p53 in response to stress such as. Podosomes are dynamic, shortlived, actinrich protrusions of the plasma membrane, which are thought to mediate adhesion to and, in some cases, degradation of the surrounding extracellular matrix. Cleavage at the base of the hairpin is catalyzed by drosha and results in the release of the pre mirna fig. Although the exact molecular mechanisms of mirna recruitment into exosomes are not well understood, 16 it is known that changes in tp53 expression in a cancer cell can alter the.
Regulation of primary microrna processing creugny 2018. Suzuki hi, yamagata k, sugimoto k, iwamoto t, kato s and miyazono k. In the long term, agerelated cardiovascular diseases cvds. Nmslmediated tertiary structure represses mir92a drosha processing and mrna targeting. The publisher apologizes for any inconvenience this may cause. Afanasyeva, ea, pieter mestdagh, candy kumps, jo vandesompele, v ehemann, j theissen, mark zapatka, et al. References suzuki hi, yamagata k, sugimoto k, iwamoto t, kato s, miyazono k. In addition, several reports showed the interplay between the p53 tumor suppressor network and the mirna mediated gene regulatory system. The acetylation of k120 drove cells toward apoptosis by augmenting mature mir203 which finally led to a downregulation of its target bclw chang et al. The pri mirna hairpin is composed of a mostly ds stem region enclosed by a single stranded ss terminal loop and ss flanking regions fig.
Determinants of microrna processing inhibition by the. An amphiphilic peptide induces apoptosis through the. The p53 protein is known to activate the transcription of a subset of mirnacoding genes 1,3,5. Xenografts of hct116 sh p53 cells grew significantly faster than those of hct116 sh. Emerging paradigms of regulated microrna processing. Modulation of microrna processing by p53 toru suzuki, hiroshi tamada department of cancer biology, graduate school of medicine, kyoto university, kyoto, japan this article has been withdrawn at the request of the editor. However, more recent studies have shown coexpression of mirna5p and 3p, albeit in different concentrations, in cancer cells targeting different sets of transcripts. The spatiotemporal control of mirna abundance is made possible, in part, by the regulation of its biosynthesis pathway, where alterations can lead to global mirna deregulation. Disruption of p53 function is a fundamental event in the development of most cancers. Mar 12, 2015 nutlin3 induces p53 regulated mirnas and p53 responsive genes. However, the mechanisms stabilizing or reducing these small rnas remains poorly understood.
Wildtype p53 suppresses the epithelialmesenchymal transition and stemness in pc3 prostate cancer cells by modulating mir. Nrs can regulate mirna expression either at the transcriptional level, or through posttranscriptional maturation by interacting with mirna processing factors. Dicer is a central regulator of microrna maturation. Jul 23, 2009 the p53 tumour suppressor is a well known transcriptional activator with many growth suppressive targets.
The microprocessor can be modulated by proteins like a snrnps in dark blue and. Regulation of microrna expression and function by nuclear. Thus, gain of function mutant p53 proteins can exert their oncogenic activities through the modulation of both noncoding and coding regions of human genome. Cleavage of pribantam or primir30a yielded the expected end. Protein levels of p53 and downstream targets were analyzed after enforced mir8855p expression to assess mir8855p influence on p53 regulation and function. Here we show that two p53 responsive mirnas utilize distinct but complementary mechanisms to promote cancer cell quiescence by facilitating stabilization of p27. Similarly, the p53 tumor suppressor gene is the most frequently mutated gene in human cancer, and its loss or mutation leads to tumor formation in. Primary microrna processing is functionally coupled to rnap. Microrna 34 targets notch, hmga2 and bcl2 genes involved in selfrenewal and survival of. Micro rna 145 targets the insulin receptor substrate1 and inhibits the growth of colon cancer cells. To what extent these phenomena play a role in the heart remains unclear. Together, mir143145, mdm2 and p53 form a regulatory feedback loop that was shown to modulate cell proliferation and apoptosis in the head and neck squamous cell carcinomas zhang et al. The processing of plant precursors by multiple dcl1 cuts has been also observed in other cases 28, 82 and so far, is a distinctive feature not present in animal precursors. Modulation of microrna expression in dna damage response.
Ars2 links the nuclear capbinding complex to rna interference and cell proliferation. Micrornas from this family are produced from the 3 arm of the precursor hairpin. Asoke banerji phytochemistry, amrita school of biotechnology who is leading the efforts in the extraction and purification of natural products from various plant sources, we plan to test these compounds on the expression of gelatinases mmp2 and. Read p53 induced microrna 107 inhibits proliferation of glioma cells and downregulates the expression of cdk6 and notch2, neuroscience letters on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Shi b, sepplorenzino l, prisco m, linsley p, deangelis t, baserga r. Microrna mir92a1 biogenesis and mrna targeting is modulated. Overexpression of tp53 mutationassociated microrna182. The mir2 microrna family includes the microrna genes mir2 and mir mipf0000049. These findings suggest that transcriptionindependent modulation of mirna biogenesis is. Nuclear receptors nrs are ligandactivated transcription factors that regulate gene transcription by binding to the promoter region or by interacting with other transcription factors. Microrna 21 mir21 is overexpressed virtually in all human cancers and displays oncogenic activity in a transgenic murine model. Lin28 inhibits the maturation of the let7 family but not other mirnas, yet a mechanistic explanation for this selectivity is unknown.
Despite improvements in diagnosis and treatment, many elderlies suffer from cardiovascular problems that are much more frequent in an older, more fragile organism. Disruption of p53 function is a fundamental event in. The two founding members of the microrna family were originally identified in caenorhabditis elegans as genes that were required for the timed. Rather, processing at the drosha step was triggered. Finally the repression of mirna processing by the partial depletion of. In principle, the processing of mir319 and mir159 precursors might lead to the accumulation of several mirnas. Regulation of mirna expression can occur both at the transcriptional level and at the posttranscriptional level during mirna processing. Genome wide expression profiling of p53 regulated mirnas in. In 2009, in the same manuscript concerning the role of wtp53 in mirna processing, suzuki and collaborators provide evidences that the overexpression of three tumor gof p53 mutants in the dna binding domain r273h, r175h, c5y in colon carcinoma hct p53 null cell line, decreases the ability of an ectopic expressed drosha to bind p68 and primirnas, leading to inhibition of processing. Similar to many cellular pathways, mirna processing and function can be globally or. Apart from global modulation of mirna biogenesis, mutant p53 also affects expression of.
The pri to pre mirna processing stepdrosha and cofactors. Based on the clinical results obtained in vetreated chronic hbv carriers, we provide a reliable hypothesis for the possible role of this vitamin in the modulation of host mirna profiles perturbed by this viral pathogen and in the regulation of some cellular mirna with a suggested potential antihbv activity. Hannon micrornas are a family of small, noncoding rnas that regulate gene expression in a sequencespecific manner. Using this assay, we establish an essential function of heme in mirna maturation, a provocative idea suggested by previous biochemical studies. Based on our findings, we propose a novel brca1 function in the regulation of mirna processing. In addition to control mirna biogenesis, the p53 family can directly affect the expression of specific mirnas table 1. Here we identify mammalian immune regulator mcpip1 zc3h12a ribonuclease as a broad suppressor of mirna activity and biogenesis, which counteracts dicer, a central ribonuclease in mirna processing. The accuracy of primirna processing by our immunoaf. Acetylation of p53 at lysine 120 after genotoxic stress was shown to be crucial for the association of p53 with the microprocessor complex and the modulation of microrna maturation. Modulation of microrna processing by p53 hiroshi i. However, little is known about mechanisms regulating its expression in development or disease.
Genetics and molecular biology of epsteinbarr virus. Microrna1282 targets the transcriptional repressor e2f5. Identification and analysis of p53 mediated competing endogenous rna network in human hepatocellular carcinoma. Microrna control of p53 juan liu, cen zhang, yuhan zhao, and zhaohui feng department of radiation oncology, rutgers cancer institute of new jersey, rutgers, state university of new jersey, new brunswick 08903, new jersey abstract tumor suppressor p53 plays a central role in tumor suppression. However, some more recent studies suggest that the latter is the more common mechanism for mirna.
Emerging evidence indicates that micrornas mirnas play essential roles in regulating osteoblastogenesis and bone formation. At the same time, mirnas could be a new group of regulators for p53, joining a panel of. Microrna mir8855p targets cdk2 and mcm5, activates p53 and inhibits proliferation and survival. Thus, the major aim of this thesis is to uncover the expression and processing variations of mirnas and mrna 3ends, and evaluate their changes during cardiac hypertrophy. Here we show that p53r175h, a hotspot p53 mutant, induces microrna mirna1282 expression.
India is rich in plant biodiversity, and that has been utilized extensively in traditional medicine. Biogenesis and the regulation of the maturation of mirnas. Alternative processing of primary microrna transcripts by. Modulation of microrna expression and function by adars.
Small rnas with a big role in gene regulation lin he and gregory j. Frequent coexpression of mirna5p and 3p species and cross. Pdf tumor suppressor p53 plays a central role in tumor suppression. Brca1 regulates microrna biogenesis via the drosha. These findings suggest that transcriptionindependent modulation of mirna biogenesis is intrinsically embedded in a tumour suppressive program governed by p53.
Tp53 was reported to facilitate the processing of primary mirnas to. Microrna and mrna processing variations in normal and. Manipulating micrornas for the treatment of malignant. Microrna control of podosome formation in vascular smooth. Micrornas mirnas are versatile regulators of gene expression and undergo complex maturation processes. However, specific genetic mechanisms of pathogenesis have been difficult to identify.
We have developed a robust method that faithfully measures pri mirna processing efficiency in live cells. A p53responsive mirna network promotes cancer cell. Read overexpression of tp53 mutationassociated microrna 182 promotes tumor cell proliferation and migration in head and neck squamous cell carcinoma, archives of oral biology on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Lineagespecific transcriptional regulation of dicer by mitf. Mir2 is widespread in invertebrates, and it is the largest family of micrornas in the model species drosophila melanogaster. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions.
In hct116 cells and human diploid fibroblasts, p53 interacts with the drosha processing complex through the asso ciation with deadbox rna helicase p68. While profiling mirna expression in differentiating melanocytes, two populations were observed. Signalingmediated regulation of microrna processing. B regulate microrna34c expression in porcine ovarian granulosa cells.
If the nmslmir19b interaction is important for the folding of the mir17. Cancer cells in quiescence g 0 phase are resistant to death, and reentry of quiescent cancer cells into the cellcycle plays an important role in cancer recurrence. Yiming zhang, ran kang, wenrong liu, yalan yang, ruofan ding, qingqing huang, junhua meng, lili xiong, zhiyun guo. Epsteinbarr virus, a ubiquitous human herpesvirus, is associated through epidemiologic evidence with common autoimmune syndromes and cancers. Moore abstractalthough the roles of the sterol response element binding protein1. In addition, several reports showed the interplay between the p53 tumor suppressor network and the mirnamediated gene regulatory system. The microrna mirna biogenesis pathway is a series of biochemical steps that converts the primary mirna transcript primirna to the biologically active, mature mirna kim et al. Microrna processing can also be affected directly or.
Ars2 regulates both mirna and sirna dependent silencing and suppresses rna virus infection in. Modulation of microrna and transcriptional regulation of mmp. Possible role of tocopherols in the modulation of host. Small rna sequencing and functional characterization reveals microrna 143 tumor suppressor activity in. Processing of microrna primary transcripts requires heme.
Multiple micrornas modulate p21cip1waf1 expression by directly targeting its 30 untranslated region swu1,2 4, s huang2 4, j ding2, y zhao2, l liang2, t liu3, r zhan1 and x he2 1department of hematology, fujian medical university union hospital, fujian institute of hematology, fuzhou, china. The two riiids form an intramolecular dimer to create one processing center containing two catalytic sites. Posttranscriptional regulation of mirnas in the dna damage. Second, p53 promotes the droshamediated processing and maturation of certain mirnas with growthsuppressive function, including mir161, mir143 and mir145. A mirna precursor generally gives rise to one major mirna species derived from the 5 arm, and are called mirna5p. Mammalian ape1 controls mirna processing and its interactome is. First, we examined the processing of two primirna substrates that were labeled at their 5 or 3 termini fig. Suzuki hi, yamagata k, sugimoto k, iwamoto t, kato s, miyazono k. Processing of plant microrna precursors briefings in. In the case of mir16, the significant inhibitory effects on tumor growth following. Microrna mir92a1 biogenesis and mrna targeting is modulated by a tertiary contact within the mir17 92 microrna cluster steven g. Microrna mir8855p targets cdk2 and mcm5, activates p53 and. One of the best characterized examples is the induction of mir34 by p53. Navigating the micronome using multiple microrna prediction.
Overview of microrna processing, from transcription to the formation of the effector complex. Identification and analysis of p53mediated competing. The scope of the journal covers all experimental mirna research and applied research in health and disease, including therapeutic, biomarkers, and diagnostic applications of mirna. At the same time, p53 monitors the maturation of mirnas. Modulation of microrna processing by p53 researchgate. Wildtype p53 suppresses the epithelialmesenchymal transition and. There is also increasing evidence that the regulation of the small rna biogenesis pathway is crucial to cellcycle regulation and responds to pathogen attack. Micrornas as key effectors in the p53 network sciencedirect. The characterized first step is the recognition of the canonical stemloop structure of the mirna by the microprocessor complex. The role of phytochemicalmodulated expression of mirnas through the regulation of proteins involved in mirna processing has been recently investigated. This article has been withdrawn at the request of the editor.
Supporting information additional supporting information may be found online in the supporting information section at the end of the article. Micrornas and essential components of the microrna processing machinery are not encoded in the genome of the ctenophore mnemiopsis leidyi maxwell et al. We recently found that p53 modulates mirna maturation at the processing step of primary mirna transcripts, unraveling a novel function of p53. The p53 tumour suppressor is a well known transcriptional activator with many growth suppressive targets. Ddx5 and facilitating droshamediated primirna processing. Interaction of the oncogenic mir21 microrna and the p53. However, the role of mirna in osteoblast mechanotransduction remains to be. Pten modulates mir21 processing via rnaregulatory protein. Oxidation of mirnas may also regulate cellular events by modulating their effects on the specific target gene. Micrornas and essential components of the microrna processing. Recent studies have elucidated specific aspects of the wellregulated nature of mirna processing involving various regulatory proteins, editing of mirna transcripts, and cellular location.