MiRNA-27a controls FBW7/hCDC4-dependent cyclin E degradation and cell cycle progression

Mikael Lerner, Josefin Lundgren, Shahab Akhoondi, Angelina Jahn, Hwee-Fang Ng, Farhad Akbari Moqadam, Joachim A F Oude Vrielink, Reuven Agami, Monique L Den Boer, Dan Grandér, Olle Sangfelt

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

The F-box protein FBW7/hCDC4 is a tumor suppressor that acts as the substrate recognition component of an SCF ubiquitin ligase that targets numerous oncoproteins for proteasomal degradation. In this study, we investigated whether FBW7 is regulated by microRNAs, using a screen combining bioinformatic analysis, luciferase reporters and microRNA libraries. The ubiquitous miR-27a was identified as a major suppressor of FBW7 and in line with this, miR-27a prohibited ubiquitylation and turnover of the key FBW7 substrate cyclin E. Notably, we found that miR-27a only suppresses FBW7 during specific cell cycle phases, relieving its negative impact at the G1 to S-phase transition, prior to cyclin E protein degradation. We also demonstrate that attenuation of FBW7 by miR-27a overexpression leads to improper cell cycle progression and DNA replication stress, consistent with dysregulation of cyclin E expression. Finally, in the context of human cancer, miR-27a was discovered to be generally overexpressed in pediatric B-ALL and its expression to be inversely correlated with that of FBW7 in hyperdiploid cases of B-ALL. These data provide evidence for microRNA-mediated regulation of FBW7, and highlight the role of miR-27a as a novel factor fine-tuning the periodic events regulating cell cycle progression.

Originele taal-2Engels
Pagina's (van-tot)2172-83
Aantal pagina's12
TijdschriftCell cycle (Georgetown, Tex.)
Volume10
Nummer van het tijdschrift13
DOI's
StatusGepubliceerd - 1 jul. 2011
Extern gepubliceerdJa

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