Differential Regulation of microRNAs by p53 Revealed by Massively Parallel Sequencing: miR-34a is a p53 Target That Induces Apoptosis and G1-arrest

By V. Tarasov, P. Jung, B. Verdoodt, D. Lodygin, A. Epanchintsev, A. Menssen, Gunter Meister, H. Hermeking. Cell Cycle, 2007

982 citations recorded by the source corpus.

In a genome‑wide screen for microRNAs regulated by the transcription factor encoded by the p53 tumor suppressor gene we found that after p53‑activation the abundance of thirty-four miRNAs was significantly increased, whereas sixteen miRNAs were suppressed. The induction of miR‑34a was most pronounced among all differential regulations. Also expression of the primary miR‑34a transcript was induced after p53 activation and by DNA damage in a p53‑dependent manner. p53 occupied an evolutionarily conserved binding site proximal to the first non-coding exon of miR‑34a. Ectopic miR‑34a induced apoptosis and a cell cycle arrest in the G1-phase, thereby suppressing tumor cell proliferation. Other p53‑induced miRNAs identified here may also have tumor suppressive potential as they are known to suppress the anti‑apoptotic factor Bcl2 (miR‑15a/16) and the oncogenes RAS and HMGA2 (let‑7a). Our results for the first time directly integrate the regulation of miRNA expression into the transcriptional network regulated by p53. siRNAs corresponding to p53‑induced miRNAs may have potential as cancer therapeutic agents as RNA interference based therapies are currently emerging.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7d91451f45d1a4d30c3074be218f15b5d9c1e0e4

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Citations in the corpus

MicroRNAs in stress signaling and human disease (2012, background): “…the miR-34a and miR-34b/miR-34c transcription units which then are able to mediate some aspects of the cellular response to p53 activation, including cell-cycle arrest and apoptosis (Bommer et al., 2007; Chang et al., 2007; He et al., 2007; Raver-Shapira et al., 2007; Tarasov et al., 2007).”
miR-34 – a microRNA replacement therapy is headed to the clinic (2012, background): “…in the execution of molecular programs directed by p53 (Bommer et al., 2007; Chang et al., 2007; He et al., 2007; Raver-Shapira et al., 2007; Tarasov et al., 2007). miR-34a represses BCL2 and survivin; however, it is possible that other mechanisms contribute to the pro-apoptotic functions…”
MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells (2009, positive): “Recently, the three members of the miR-34 family were found to be directly regulated by p53 and the functional activity of miR-34 indicated a potential role as a tumor suppressor [6,7,8,9,10,11,12].”
Blinded by the Light: The Growing Complexity of p53. (2009, background): “…microRNAs (miRNAs), most dramatically the miR-34 locus consisting of miR-34a, miR-34b, and miR-34c (Bommer et al., 2007; Chang et al., 2007; Corney et al., 2007; He et al., 2007; Raver-Shapira et al., 2007; Tarasov et al., 2007; Tazawa et al., 424 Cell 137, May 1, 2009 ©2009 Elsevier Inc. 2007).”
Targeting p53 pathways: mechanisms, structures and advances in therapy (2023, background): “73,74 In the exogenous apoptotic pathway, p53 induces the expression of the death receptors Fas/Fas ligand and KILLER/DR5 located on the cell membrane, which activates caspase 8 and leads to apoptosis.”
A human snoRNA with microRNA-like functions. (2008, neutral): “Germany) and has been described earlier (Tarasov et al., 2007).”
MicroRNA and cancer (2012, background): “…various target genes in promoting cell proliferation and inhibiting cell cycle arrest and apoptosis, it is plain that miR-34 induction by p53 complements its role in the negative regulation of cell growth (Chang et al., 2007; Hermeking, 2009, 2012; Raver-Shapira et al., 2007; Tazawa et al., 2007).”
Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs (2010, methodology): “Small RNA cloning was carried out by Vertis Biotechnology (Weihenstephan, Germany) and has been described earlier (36).”
MicroRNAs in development and disease. (2011, background): “Notably, transcription of the miR34a gene is also dependent on p53 and is accordingly depressed in cancer cells lacking p53 (85, 118, 239, 503, 599).”
MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death (2008, background): “Five groups independently identified miR-34 as a target for p53 (Bommer et al., 2007; Chang et al., 2007; He et al., 2007; Raver-Shapira et al., 2007; Tarasov et al., 2007).”