Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied 613 genes which regulate immunity and, utilizing predictive algorithms, identified 285 genes as microRNA (miRNA or miR) targets. Of these, approximately 250 are newly predicted gene-miR interactions. The frequency of predicted miRNA binding sites in immune gene 3'UTRs indicated preferential targeting of immune genes compared to the genome. Major targets include transcription factors, cofactors and chromatin modifiers whereas upstream factors, such as ligands and receptors (cytokines, chemokines and TLRs), were, in general, non-targets. About 10% of the immune genes were 'hubs' with eight or more different miRNAs predicted to target their 3'UTRs. Hubs were focused on certain key immune genes, such as BCL6, SMAD7, BLIMP1, NFAT5, EP300 and others. NF-kappaB and p53 do not themselves have binding sites for miRNAs but rather these pathways are targeted by miRNAs at downstream sites. MHC class II genes lacked miRNA targets but binding sites were identified in the CIITA gene and were shown experimentally to repress IFN-gamma-induced MHC class II activation. Unexpectedly, factors involved in regulating message stability via AU-rich elements (ARE) were heavily targeted. Moreover, multiple components involved in the generation and effector functions of miRNAs (Dicer and Argonautes) were themselves miRNA targets suggesting that a subset of miRNAs may indirectly control their own production as well as other miRNAs.
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PMID:MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components. 1806 76

Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablation of Dicer and loss of mature miRNAs in embryonic fibroblasts up-regulated p19(Arf) and p53 levels, inhibited cell proliferation, and induced a premature senescence phenotype that was also observed in vivo after Dicer ablation in the developing limb and in adult skin. Furthermore, deletion of the Ink4a/Arf or p53 locus could rescue fibroblasts from premature senescence induced by Dicer ablation. Although levels of Ras and Myc oncoproteins appeared unaltered, loss of Dicer resulted in increased DNA damage and p53 activity in these cells. These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19(Arf)-p53 signaling, and induces senescence in primary cells.
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PMID:Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells. 1859 25

Dicer is a key dsRNase in RNA interference, and Wig-1 is a p53-induced zinc finger protein with dsRNA-binding activity. In this report, we demonstrated a direct interaction between Dicer and Wig-1. Dicer associated with Wig-1, which was expressed as a glutathione S-transferase fusion protein, in a dose-dependent manner by GST pull-down assay. In a reciprocal experiment, Wig-1 appeared to compete with GST-eIF2C1 for the binding of Dicer. Far-western analysis showed that Dicer could bind to GST-Wig-1 directly. Furthermore, it was found that Wig-1 could increase the dsRNase activity of Dicer in vitro. Our findings raise the possibility that Dicer and Wig-1 may play a common role in dsRNA-related gene regulation.
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PMID:[Dicer interacts with Wig-1 protein]. 1912 73

Dicer, a ribonuclease essential for miRNA processing, is expressed abundantly in developing mouse cornea and lens. We studied the roles of Dicer and miRNAs in eye development by conditionally deleting the Dicer gene in the mouse lens and corneal epithelium. Adult Dicer conditional null (DicerCN) mice had severe microphthalmia with no discernible lens and a poorly stratified corneal epithelium. Targeted deletion of Dicer effectively inhibited miRNA processing in the developing lens at 12.5 day of embryogenesis (E12.5). Lens development initiated normally but underwent progressive dystrophy between E14.5 and E18.5. Microarray analysis revealed activation of P53 signaling in DicerCN lenses at E13.5, consistent with increased apoptosis and reduced cell proliferation between E12.5 and E14.5. Expression of Pax6 and other lens developmental transcription factors were not greatly affected between E12.5 and E14.5 but decreased as the lens degenerated. Our data indicated an indispensible role for Dicer and miRNAs in lens and corneal development.
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PMID:Targeted deletion of Dicer disrupts lens morphogenesis, corneal epithelium stratification, and whole eye development. 1968 Nov 34

Urothelial carcinoma of the bladder (UCC) is a common disease that arises by at least two different molecular pathways. The biology of UCC is incompletely understood, making the management of this disease difficult. Recent evidence implicates a regulatory role for microRNA in cancer. We hypothesized that altered microRNA expression contributes to UCC carcinogenesis. To test this hypothesis, we examined the expression of 322 microRNAs and their processing machinery in 78 normal and malignant urothelial samples using real-time rtPCR. Genes targeted by differentially expressed microRNA were investigated using real-time quantification and microRNA knockdown. We also examined the role of aberrant DNA hypermethylation in microRNA downregulation. We found that altered microRNA expression is common in UCC and occurs early in tumorogenesis. In normal urothelium from patients with UCC, 11% of microRNAs had altered expression when compared with disease-free controls. This was associated with upregulation of Dicer, Drosha, and Exportin 5. In UCC, microRNA alterations occur in a tumor phenotype-specific manner and can predict disease progression. High-grade UCC were characterized by microRNA upregulation, including microRNA-21 that suppresses p53 function. In low-grade UCC, there was downregulation of many microRNA molecules. In particular, loss of microRNAs-99a/100 leads to upregulation of FGFR3 before its mutation. Promoter hypermethylation is partly responsible for microRNA downregulation. In conclusion, distinct microRNA alterations characterize UCC and target genes in a pathway-specific manner. These data reveal new insights into the disease biology and have implications regarding tumor diagnosis, prognosis and therapy.
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PMID:Distinct microRNA alterations characterize high- and low-grade bladder cancer. 1984 43

The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3'UTR) of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63(-/-) and dicer(-/-) mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into how p53, p63, and p73 regulate the components of the miRNA processing; and how p53, TA-p63, and TA-p73 regulated miRNAs inhibit tumorigenesis, EMT, metastasis, and cancer stem cell proliferation.
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PMID:The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex. 2048 46

Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.
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PMID:TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. 2096 48

Thrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis encoded by the THBS1 gene, whose promoter is activated by p53. In advanced colorectal cancers (CRC), its expression is sustained or even slightly increased despite frequent loss of p53. Here, we determined that in HCT116 CRC cells, p53 activates the THBS1 primary transcript, but fails to boost THBS1 mRNA or protein levels, implying posttranscriptional regulation by microRNAs (miRNA). In a global miRNA gain-of-function screen done in the Dicer-deficient HCT116 variant, several miRNAs negatively regulated THBS1 mRNA and protein levels, one of them being miR-194. Notably, in agreement with published data, p53 upregulated miR-194 expression in THBS1 retrovirus-transduced HCT116 cells, leading to decreased TSP-1 levels. This negative effect was mediated by a single miR-194 complementary site in the THBS1 3'-untranslated region, and its elimination resulted in TSP-1 reactivation, impaired angiogenesis in Matrigel plugs, and reduced growth of HCT116 xenografts. Conversely, transient overexpression of miR-194 in HCT116/THBS1 cells boosted Matrigel angiogenesis, and its stable overexpression in Ras-induced murine colon carcinomas increased microvascular densities and vessel sizes. Although the overall contribution of miR-194 to neoplastic growth is context dependent, p53-induced activation of this GI tract-specific miRNA during ischemia could promote angiogenesis and facilitate tissue repair.
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PMID:p53-responsive miR-194 inhibits thrombospondin-1 and promotes angiogenesis in colon cancers. 2202 25

MET, a receptor protein tyrosine kinase activated by hepatocyte growth factor (HGF), is a crucial determinant of metastatic progression. Recently, we have identified p53 as an important regulator of MET-dependent cell motility and invasion. This regulation occurs via feedforward loop suppressing MET expression by miR-34-dependent and -independent mechanisms. Here, by using Dicer conditional knockout, we provide further evidence for microRNA-independent MET regulation by p53. Furthermore, we show that while MET levels increase immediately after p53 inactivation, mutant cells do not contain active phosphorylated MET and remain non-invasive for a long latency period at contrary to cell culture observations. Evaluation of mouse models of ovarian and prostate carcinogenesis indicates that formation of desmoplastic stroma, associated production of HGF by stromal cells and coinciding MET phosphorylation precede cancer invasion. Thus, initiation mutation of p53 is sufficient for preprogramming motile and invasive properties of epithelial cells, but the stromal reaction may represent a critical step for their manifestation during cancer progression.
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PMID:MET-dependent cancer invasion may be preprogrammed by early alterations of p53-regulated feedforward loop and triggered by stromal cell-derived HGF. 2207 25

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Alterations in microRNAs (miRNAs) expression have been proposed to play a role in CLL pathogenesis. Dicer and Drosha are the main regulators of miRNA biogenesis, and deregulation of their expression has been indicated as a possible cause of miRNA alterations observed in various cancers. To investigate the role of Dicer and Drosha in CLL, we assessed the expression of Dicer and Drosha and their correlation with other prognostic factors, including Binet stages, immunoglobulin heavy chain variable gene (IGHV) mutation status, TP53 mutation status, ZAP-70 protein and CD38 expression level in 165 CLL patients by using real-time polymerase chain reaction methods. Patients with unmutated IGHV genes had significantly lower expression of Dicer than patients with IGHV mutations. The lower expression level of Dicer was also significantly associated with higher level of CD38 and ZAP-70, and more aggressive Binet stage. We also analyzed Dicer expression in different cytogenetic subgroups. Lower Dicer level was found in patients with unfavorable cytogenetic aberrations (deletion in 17p13 or 11q22.3) in contrast to higher level in good risk cytogenetics (deletion in 13q14 as the sole abnormality). Furthermore, the lower expression of Dicer in CLL shows a strong association with shorter overall survival (OS) (P = 0.0046) as well as with reduced treatment free survival (TFS) (P = 0.0006). By contrast, no differences in the expression of Drosha among these groups of patients were observed. Our data suggest that Dicer expression may play an important role in the progression and prognosis of CLL.
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PMID:Downregulated Dicer expression predicts poor prognosis in chronic lymphocytic leukemia. 2232 Mar 15


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