An autoregulatory network between menin and pri-miR-24-1 is required for the processing of its specific modulator miR-24-1 in BON1 cells.
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary cancer complex syndrome manifesting a variety of endocrine and non-endocrine neoplasms and lesions. MEN1 is characterized by tumours of the parathyroids, of the neuroendocrine cells of the gastroenteropancreatic tract, and of the anterior pituitary. The MEN1 gene, a tumour suppressor gene, encodes the menin protein. Loss of heterozygosity (LOH) at 11q13 is typical of MEN1 tumours in agreement with Knudson's two-hit hypothesis. We previously showed that the MEN1 parathyroid tumorigenesis is under the control of an "incoherent feedback loop" between miR-24-1 and the menin protein that generates a "Gene Regulatory Network" (GRN) that mimics the second hit of Knudson's hypothesis and that could buffer the effect of the stochastic factors that contribute to the onset and progression of this disease. Here we show, in the BON1 cell line derived from lymphnode metastasis of a human carcinoid tumour of the pancreas, that menin binds specifically to the primary RNA sequence pri-miR-24-1 by promoting the miR-24-1 biogenesis. Network simulation showed a new feed-forward loop between menin, microRNA-24-1 and Musashi-1 proteins. This result shows a novel mechanism whereby menin, a RNA-binding protein, facilitates the processing of its specific miRNA by regulating the dynamics of the menin-miR-24 Gene Regulatory Network at the level of pri-miRNA processing.
Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy. eluzi@unifi.it francesca.marini@dmsc.unifi.it simone.ciuffi@unifi.it gianna.galli@unifi.it marialuisa.brandi@unifi.it.
Ettore
E
Luzi
Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy. eluzi@unifi.it francesca.marini@dmsc.unifi.it simone.ciuffi@unifi.it gianna.galli@unifi.it marialuisa.brandi@unifi.it.
Francesca
F
Marini
Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy. eluzi@unifi.it francesca.marini@dmsc.unifi.it simone.ciuffi@unifi.it gianna.galli@unifi.it marialuisa.brandi@unifi.it.
Simone
S
Ciuffi
Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy. eluzi@unifi.it francesca.marini@dmsc.unifi.it simone.ciuffi@unifi.it gianna.galli@unifi.it marialuisa.brandi@unifi.it.
Gianna
G
Galli
Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy. eluzi@unifi.it francesca.marini@dmsc.unifi.it simone.ciuffi@unifi.it gianna.galli@unifi.it marialuisa.brandi@unifi.it.
Maria Luisa
ML
Brandi
D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D018895:Microsatellite Repeats; D009154:Mutation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D014157:Transcription Factors / Q000378:metabolism
C105373:MEN1 protein, human; C543845:MIRN24 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors