In human cells, master watchman p53 interacts with p68 and p72 rna helicases. In this study, we used a highthroughput luciferase reporter screen to demonstrate that p53 can be regulated by microrna 1285 mir1285. Molecular mechanism of diabetic cardiomyopathy and. The tumor suppressor gene p53 is altered in more than half of human cancers 1620. Viswanathan sr, daley gq, gregory ri 2008 selective blockade of microrna processing by lin28. These findings have prompted a great deal of investigation into. Induction of amphiregulin by p53 promotes apoptosis via. Signalingmediated regulation of microrna processing. Micrornas mirnas are small noncoding rnas with 1925 bases of length that control gene expression by destroying messenger rna or inhibiting its translation.
It plays an important role in cell senescence in most murine tissues. Microrna21 mir21 is overexpressed virtually in all human cancers and displays oncogenic activity in a transgenic murine model. Jpg, made by narayanese talk contribs after an illustration in esquelakerscher a, slack fj 2006. This gene is expressed in breast and other tissues, where it helps to repair damaged genomes and disrupts cells when the genome cannot be repaired shen et al. The role of micrornas as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma hcc. Moore abstractalthough the roles of the sterol response element binding protein1 srebp1 and srebp2 transcription factors in regulating fatty acid and cholesterol synthesis and uptake have been known for some time, it was recently discovered that 2.
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. May 28, 2010 the wellknown tumor suppressor p53 plays critical roles in the modulation of multiple cellular processes. The two founding members of the microrna family were originally identified in caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Interestingly, another report showed a novel mechanism of posttranscriptional regulation of mir145 that occurs via p53 mediated rna processing suzuki et al. Brca1 regulates microrna biogenesis via the drosha. These findings suggest that transcriptionindependent modulation of mirna. Cancers free fulltext the role and function of microrna. The two riiids form an intramolecular dimer to create one processing center containing two catalytic sites. Despite being well characterized, the fundamental mechanisms leading to dcm are still elusive. 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. Diabetic cardiomyopathy dcm is a chronic complication in individuals with diabetes and is characterized by ventricular dilation and hypertrophy, diastolic dysfunction, decreased or preserved systolic function and reduced ejection fraction eventually resulting in heart failure. Disruption of p53 function is a fundamental event in the development of most cancers. In multiple myeloma mm, the expression of several mirnas, such as mir15a and mir16, is markedly decreased and their target. In just a few short years micrornas have become firmly established as key molecular components of the cell in both normal and pathologic states 1.
Modulation of microrna processing by p53 article pdf available in nature 4607254. Current view of microrna processing shuai jiang, wei yan. While their roles have been attracting more attention in connection with tumor development, the mechanisms. More than half of human cancers, of a wide variety of types, harbor p53 tp53 mutations, and inheritance of a mutant p53 allele predisposes humans to the lifraumeni cancer syndrome olivier et al. Suzuki hi1, yamagata k, sugimoto k, iwamoto t, kato s, miyazono k. Micrornas mirnas have emerged as key posttranscriptional regulators of gene expression, involved in diverse physiological and pathological processes. Modulation of microrna expression and function by adars. As a result, these mrna molecules are silenced, by one or more of the following. Tumor suppressor mir22 determines p53dependent cellular. Cancer in particular has been a major focus of microrna research over the past decade, and many studies have demonstrated the importance of micrornas in cancer biology through controlling expression of their target mrnas to facilitate tumor growth. Sep 20, 2011 the tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the dna repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. This is a pdf file of an unedited manuscript that has been accepted for publication. Histone deacetylase 1 enhances microrna processing via.
In addition, several reports showed the interplay between the p53 tumor suppressor network and the mirna mediated gene regulatory system. Molecular mechanism of diabetic cardiomyopathy and modulation. Accordingly, coimmunoprecipitation experiments as well as in vitro drosha processing assays. The p53 is an important regulator in the process of cell apoptosis. Micrornas mirnas are pivotal regulators involved in various biological functions through the posttranscriptional regulation of gene expression. The pivotal tumor suppressive role of p53axis is indicated by the presence of inactivating mutations in tp53 gene in nearly all cancers. Sirt1 modulates mirna processing defects in p53mutated human keratinocytes. A recent report has suggested a role for mir33 in regulating stem cell selfrenewal via downregulation of p53. Regulation of primary microrna processing creugny 2018. Microrna149, a p53responsive microrna, functions as an. Signalingmediated regulation of microrna processing cancer. The first step of mirna biogenesis is the transcription from genomic dna largely by rna polymerase ii, and it generates stemloop structural primirnas with a stable 7methylguanosine cap and polya tail. Tumor suppressor p53 meets micrornas pubmed central pmc. Full text the p53microrna connection in gastrointestinal.
An amphiphilic peptide induces apoptosis through the. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers, but wt p53 is often expressed at high levels in. The pivotal tumor suppressive role of p53 axis is indicated by the presence of inactivating mutations in tp53 gene in nearly all cancers. In cellfree assays, both proteins have moderately processive atp dependent rna unwinding and annealing activities. An expanded role of p53 in the modulation of microrna expression. Jul 23, 2009 the p53 tumour suppressor is a well known transcriptional activator with many growth suppressive targets. Combinatorial analyses of the ago2 immunocomplex and gene. The primicrorna structure of mir145 has not been identified, yet it is suggested that it cotranscribed with mir143. Unequivocal confirmation of the crucial role for p53 in. Identification of new p53 target micrornas by bioinformatics. A genomic localization of mir145 gene on chromosome 5q32. Here we report the identification of the microrna mir22 as a p53 target gene that selectively determines the induction of p53dependent apoptosis by repressing p21.
Possible role of tocopherols in the modulation of host microrna with potential antiviral activity in patients with hepatitis b virusrelated persistent infection. Ijms free fulltext regulatory mechanism of microrna. Current view of microrna processing shuai jiang, wei yan, 2016. P53 aids in the assembly of the drosha complex and therefore can modulate microrna processing 81. By limiting the availability of primirnas or premirnas for processing, the. Disruption of p53 function is a fundamental event in the development of. Possible role of tocopherols in the modulation of host. Pdf modulation of microrna processing by p53 researchgate.
The publisher apologizes for any inconvenience this may cause. A close interaction between these two players, as well as the establishment of complex p53mirnas loops demonstrated the. Another link between p53 and mirnaprocessing has been observed in conditional dicer knockout mice. 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. Analysis of human cancers reveals a fundamental role for p53 in tumor suppression. Microrna mediated p53 activation by the microrna 29 mir29 family is one of the most important regulatory pathways in cancer therapeutics.
Selective activation of p53 target genes in response to various cellular stresses is a critical step in determining the ability to induce cellcycle arrest or apoptosis. Since p53 was discovered 30 years ago, a tremendous amount of work. The wellknown tumor suppressor p53 plays critical roles in the modulation of multiple cellular processes. Suzuki hi et al 2009 modulation of microrna processing by p53. Suzuki hi, yamagata k, sugimoto k, iwamoto t, kato s, miyazono k. Jul 23, 2009 these findings suggest that transcriptionindependent modulation of mirna biogenesis is intrinsically embedded in a tumour suppressive program governed by p53.
Micrornas mirnas modulate a broad range of gene expression patterns during. Microrna modulation of cholesterol homeostasis carlos ferna. Tumor suppressor p53 is the most frequently mutated gene in human tumors. Brca1 forms a large multiprotein complex known as the brca1associated genome. The regulation of p53 is complicated and remains elusive. Full text the p53microrna connection in gastrointestinal cancer. Dysregulation of the multiple processing steps in mature mirna biogenesis can also cause alterations in mirna expression in cancer. Interaction of the oncogenic mir21 microrna and the p53.
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 mice. The study of the p53 gene transcriptional networks continues to raise particular interest in the field due to the increasing complexity of regulatory circuits and the functions of the extensive list of target genes spanning a myriad of different biological pathways. Although ser46 phosphorylation is a critical modification for apoptosis induction, a molecular mechanism by which ser46phosphorylated p53 induces apoptosis remains unclear. The p53 tumour suppressor is a well known transcriptional activator with many growth suppressive targets. Recent studies have demonstrated that mirnas interact with p53 and its network at. In multiple myeloma mm, the expression of several mirnas, such as mir15a and mir16, is markedly decreased and their. Conversely mutant p53 generally subverts tumour suppressive tgf. Recently, a study demonstrates that activated ras can suppress mir143145 cluster through rasresponsive elementbinding protein rreb1, which represses the mir143145. Jan 14, 2014 the tumor suppressive function of p53 is tightly regulated by its posttranslational modifications. The p53 tumor suppressor gene was reported to regulate the expression of several mirnas, such as mir34, mir200. Our study reveals a previously unrecognized function of p53 in mirna processing, which may underlie key aspects of cancer biology. Regulation of mirna biogenesis as an integrated component of.
Brca1 regulates microrna biogenesis via the drosha microprocessor complex. Alterations of mirna expression and function contribute to both physiological and pathological processes such as development and cancer. Since then, hundreds of micrornas have been identified in almost all metazoan genomes, including worms, flies, plants and mammals. Wildtype p53 and smads physically interact and coordinately induce transcription of a number of key tumour suppressive genes. Modulation of microrna processing by p53 hiroshi i. 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 mismatch repair protein mutlalpha. Taken together, these findings suggest an important role of p53 in the regulation of mirna expression, and at the same time, also suggest an important role of mirnas in mediating the role of p53 in tumor suppression as a new class of p53 target genes. 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. Based on the findings from the online analysis website, mir8 targets p53 figure 6a. 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. The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the dna repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. A microrna abbreviated mirna is a small noncoding rna molecule containing about 22 nucleotides found in plants, animals and some viruses, that functions in rna silencing and posttranscriptional regulation of gene expression.
Emerging paradigms of regulated microrna processing. The deletion of p53 promotes the development of liver fibrosis and tumor progression. Considerable progress has been made in the past few years in understanding the transcription, biogenesis. Micrornamediated p53 activation by the microrna29 mir29 family is one of the most important regulatory pathways in cancer therapeutics. In this study, we used a highthroughput luciferase reporter screen to demonstrate that p53 can be regulated by microrna1285 mir1285. 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. Modulation of microrna processing by p53 pubmed result.
The ced is essential for drosha processing activity and is composed of a platform and a piwiargonautezwille paz. These findings have prompted a great deal of investigation. Recently, attention has been drawn to the role of noncoding regions of the genome in cancer pathogenesis. The p53microrna connection in gastrointestinal cancer. Utr, and mir33 transfection represses p53 expression and p53mediated apoptosis.
Genetic modulation of the let7 microrna binding to kras 3. A close interaction between these two players, as well as the establishment of complex p53 mirnas loops demonstrated the. By targeting the suppressors of p53, a tumor suppressor protein, mir29 induces apoptosis of cancer cells through p53 stabilization. Microrna 21 mir21 is overexpressed virtually in all human cancers and displays oncogenic activity in a transgenic murine model. Widespread use of microrna arrays to profile microrna expression has indicated that the levels of many micrornas are altered during development and disease. Notably, mir612, which has the same seed sequence as mir1285, cannot bind to the 3. The p53 mutants suppressed the precursor and mature mirna levels of mir161, mir143 and mir206, in comparison with the constant level of primirnas, whereas wildtype p53 increased the pre. Breast cancer 1 brca1 is a human tumor suppressor gene that plays critical roles in maintenance of genomic stability huen et al. Micrornas mirnas are a class of small, noncoding rnas critically involved in a wide spectrum of normal and pathological processes of cells or tissues by finetuning the signals important for stem cell development, cell differentiation, cell cycle regulation, apoptosis, and transformation. 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. We recently found that p53 modulates mirna maturation at the processing step of primary mirna transcripts, unraveling a novel function of p53.
Precursor micrornas are translocated to the cytoplasm to be further processed by dicer into a short, 1824 bp rna duplex. Micrornas as key effectors in the p53 network sciencedirect. An amphiphilic peptide induces apoptosis through the mir29b. Considerable progress has been made in the past few years in understanding the transcription. Here we report the identification of the microrna mir22 as a p53 target gene that selectively determines the induction of p53 dependent apoptosis by repressing p21. These findings suggest that transcriptionindependent modulation of mirna biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Here, we clarify that amphiregulin areg is specifically induced in a ser46 phosphorylationspecific manner. Canonical mirna biogenesis consists of a twostep processing, from primary transcripts primirna to precursor mirnas premirna mediated by drosha in the nucleus and from premirnas to mature mirnas mediated by dicer in the cytoplasm.
1442 1580 797 1 904 1458 816 1329 780 1084 932 545 114 1385 1027 1581 1663 1026 329 620 532 977 504 629 957 804 630 1280 1146 82 200 1167 582 498