p53-Repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation.
Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs (miRNAs) in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcriptional regulators, E2F and p53, their targets and a family of 15 miRNAs. Indicative of their significance, expression of these miRNAs is downregulated in senescent cells and in breast cancers harboring wild-type p53. These miRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these miRNAs silence antiproliferative genes, which themselves are E2F1 targets. Thus, miRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative miRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Taken together, these findings position miRNAs as novel key players in the mammalian cellular proliferation network.
Brosh
Ran
R
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Shalgi
Reut
R
Liran
Atar
A
Landan
Gilad
G
Korotayev
Katya
K
Nguyen
Giang Huong
GH
Enerly
Espen
E
Johnsen
Hilde
H
Buganim
Yosef
Y
Solomon
Hilla
H
Goldstein
Ido
I
Madar
Shalom
S
Goldfinger
Naomi
N
Børresen-Dale
Anne-Lise
AL
Ginsberg
Doron
D
Harris
Curtis C
CC
Pilpel
Yitzhak
Y
Oren
Moshe
M
Rotter
Varda
V
D000818:Animals; D001943:Breast Neoplasms; D049109:Cell Proliferation; D016922:Cellular Senescence; D050684:E2F Transcription Factors / Q000502:physiology*; D050687:E2F1 Transcription Factor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000502:physiology*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D049490:Systems Biology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53