MicroRNA501-5p induces p53 proteasome degradation through the activation of the mTOR/MDM2 pathway in ADPKD cells.

Abstract

Cell proliferation and apoptosis are typical hallmarks of autosomal dominant polycystic kidney disease (ADPKD) and cause the development of kidney cysts that lead to end-stage renal disease (ESRD). Many factors, impaired by polycystin complex loss of function, may promote these biological processes, including cAMP, mTOR, and EGFR signaling pathways. In addition, microRNAs (miRs) may also regulate the ADPKD related signaling network and their dysregulation contributes to disease progression. However, the role of miRs in ADPKD pathogenesis has not been fully understood, but also the function of p53 is quite obscure, especially its regulatory contribution on cell proliferation and apoptosis. Here, we describe for the first time that miR501-5p, upregulated in ADPKD cells and tissues, induces the activation of mTOR kinase by PTEN and TSC1 gene repression. The increased activity of mTOR kinase enhances the expression of E3 ubiquitin ligase MDM2 that in turn promotes p53 ubiquitination, leading to its degradation by proteasome machinery in a network involving p70S6K. Moreover, the overexpression of miR501-5p stimulates cell proliferation in kidney cells by the inhibition of p53 function in a mechanism driven by mTOR signaling. In fact, the downregulation of this miR as well as the pharmacological treatment with proteasome and mTOR inhibitors in ADPKD cells reduces cell growth by the activation of apoptosis. Consequently, the stimulation of cell death in ADPKD cells may occur through the inhibition of mTOR/MDM2 signaling and the restoring of p53 function. The data presented here confirm that the impaired mTOR signaling plays an important role in ADPKD.

• Authors: Lucia de Stephanis, Alessandra Mangolini, Miriam Servello, Peter C Harris, Lucio Dell'Atti, Paolo Pinton, Gianluca Aguiari
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 233 Issue 9 Pg. 6911-6924 (09 2018) ISSN: 1097-4652 [Electronic] United States
• PMID: 29323708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• MIRN501 microRNA, human
• MicroRNAs
• TSC1 protein, human
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins c-mdm2
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• ribosomal protein S6 kinase, 70kD, polypeptide 2
• PTEN Phosphohydrolase
• Proteasome Endopeptidase Complex
• Sirolimus

Topics

• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Down-Regulation (genetics)
• Gene Silencing
• Humans
• MicroRNAs (genetics, metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphorylation
• Polycystic Kidney, Autosomal Dominant (metabolism, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Stability
• Proteolysis
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Signal Transduction
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• Tuberous Sclerosis Complex 1 Protein (genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitination
• Up-Regulation (genetics)