Title of article :
Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development
Author/Authors :
Cristian and Pichiorri، نويسنده , , Flavia and Suh، نويسنده , , Sung-Suk and Rocci، نويسنده , , Alberto and De Luca، نويسنده , , Luciana and Taccioli، نويسنده , , Cristian and Santhanam، نويسنده , , Ramasamy and Zhou، نويسنده , , Wenchao and Benson Jr.، نويسنده , , Don M. and Hofmainster، نويسنده , , Craig and Alder، نويسنده , , Hansjuerg and Garofalo، نويسنده , , Michela and Di Leva، نويسنده , , Gianpiero and Volinia، نويسنده , , Stefano and Lin، نويسنده , , Huey-Jen and Perrotti، نويسنده , , Danilo and Kuehl، نويسنده , , Michael and Aqeilan، نويسنده , , Rami I. and Palumbo، نويسنده , , Antonio and Croce، نويسنده , , Carlo M.، نويسنده ,
Abstract :
Summary
tiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development.
