Negative regulation of the tumor suppressor p53 gene by microRNAs

Abstract

The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death. Recent reports have revealed that several microRNAs (miRNAs) are important components of the p53 tumor suppressor network with miR-125b and miR-504 directly targeting TP53. In this report, we use a screening method to identify that two miRNAs (miR-25 and miR-30d) directly target the 3'UTR of TP53 to down-regulate p53 protein levels and reduce the expression of genes that are transcriptionally activated by p53. Correspondingly, both miR-25 and miR-30d adversely affect apoptotic cell death, cell cycle arrest, and cellular senescence. Inhibition of either miR-25 or miR-30d expression increases endogenous p53 expression and elevates cellular apoptosis in several cell lines, including one from multiple myeloma that has little TP53 mutations. Thus, beyond miR-125b and miR-504, the human TP53 gene is negatively regulated by two more miRNAs: miR-25 and miR-30d.

MiR-125 in normal and malignant hematopoiesis

“…52 On the contrary, the U266 MM cell line transduced with miR-125b exhibited an exaggerated death rate compared with control cells by downregulation of its targets BLIMP-1 and IRF-4. The introduction of miR-125b also led to the reduced expression of SYNDECAN-1 (CD138), a cell surface molecule expressed by myeloma and primary PCs.…”

miRNAs link metabolic reprogramming to oncogenesis

“…A library screen identified a group of microRNAs regulating p53 activity. Among them, miR-30d downregulate p53 protein levels and inhibit p53-transcriptionally activated genes [121]. A screen for microRNAs against p53 activity, reported to be deregulated in human tumors, revealed the positive regulation of p53 by the miR-29 family members.…”

Plasma circulating-microRNA profiles are useful for assessing prognosis in patients with cytogenetically normal myelodysplastic syndromes

“…Among the other microRNAs that were significantly associated with myelodysplastic syndromes in this study, miR-25 is a known regulator of p53 and is involved in stem cell programming. [33][34][35] MiR-493 is a tumor suppressor that downregulates RhoC and FZD4, decreases cell motility and migration, and blocks metastatic settlement in bladder and colon cancers. 36,37 MiR-96 regulates gene expression in bone marrow stem cells, 38 is overexpressed in human cancer cells, 39 and is overexpressed in the sera of patients with lung carcinomas.…”