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Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10660-10665. doi: 10.1073/pnas.1702914114. Epub 2017 Sep 18.

Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
2
Department of Genetics, Harvard Medical School, Boston, MA 02115.
3
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215.
4
Rodent Histopathology Core, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
6
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215; peter_sicinski@dfci.harvard.edu.

Abstract

MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of the miR-34/449 family during differentiation of epithelial cells. We found that miR-34/449 suppresses the cell-cycle machinery in vivo and promotes cell-cycle exit, thereby allowing epithelial cell differentiation. Constitutive ablation of all six members of this miRNA family causes derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and entering a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues such as the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 display infertility as well as severe chronic airway disease leading to postnatal death. These results demonstrate that miRNA-mediated repression of the cell cycle is required to allow epithelial cell differentiation.

KEYWORDS:

cell cycle; ciliogenesis; cyclins; epithelial differentiation; miR-34

PMID:
28923932
PMCID:
PMC5635871
DOI:
10.1073/pnas.1702914114
[Indexed for MEDLINE]
Free PMC Article

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