Selective inhibition of microRNA accessibility by RBM38 is required for p53 activity.
MicroRNAs (miRNAs) interact with 3'-untranslated regions of messenger RNAs to restrict expression of most protein-coding genes during normal development and cancer. RNA-binding proteins (RBPs) can control the biogenesis, stability and activity of miRNAs. Here we identify RBM38 in a genetic screen for RBPs whose expression controls miRNA access to target mRNAs. RBM38 is induced by p53 and its ability to modulate miRNA-mediated repression is required for proper p53 function. In contrast, RBM38 shows lower propensity to block the action of the p53-controlled miR-34a on SIRT1. Target selectivity is determined by the interaction of RBM38 with uridine-rich regions near miRNA target sequences. Furthermore, in large cohorts of human breast cancer, reduced RBM38 expression by promoter hypermethylation correlates with wild-type p53 status. Thus, our results indicate a novel layer of p53 gene regulation, which is required for its tumour suppressive function.
Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Nicolas
N
Léveillé
Ran
R
Elkon
Veronica
V
Davalos
Vijayalaxmi
V
Manoharan
Dave
D
Hollingworth
Joachim
J
Oude Vrielink
Carlos
C
le Sage
Carlos A
CA
Melo
Hugo M
HM
Horlings
Jelle
J
Wesseling
Jernej
J
Ule
Manel
M
Esteller
Andres
A
Ramos
Reuven
R
Agami
D020413:3' Untranslated Regions; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005434:Flow Cytometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D035683:MicroRNAs / Q000235:genetics*; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D020413:3' Untranslated Regions; D035683:MicroRNAs; C515435:RBM38 protein, human; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53