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

Tobias Otto; Sheyla V. Candido; Mary S. Pilarz; Ewa Sicinska; Roderick T. Bronson; Michaela Bowden; Iga A. Lachowicz; Kristin Mulry; Anne Fassl; Richard C. Han; Emmanuelle S. Jecrois; Piotr Sicinski

doi:10.1073/pnas.1702914114

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

Tobias Otto, Sheyla V. Candido, Mary S. Pilarz, Ewa Sicinska, Roderick T. Bronson, Michaela Bowden, Iga A. Lachowicz, Kristin Mulry, Anne Fassl, Richard C. Han, Emmanuelle S. Jecrois, Piotr Sicinski^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

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.

Original language	English (US)
Pages (from-to)	10660-10665
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	40
DOIs	https://doi.org/10.1073/pnas.1702914114
State	Published - Oct 3 2017

Funding

ACKNOWLEDGMENTS. We thank Drs. Sanny S. Chung and Debra J. Wolge-muth for advice, and Carolina Vazquez, Justyna Rozycka, Anran Li, Xiaoting Li, and Jeffrey T. Czaplinski for help. This work was supported by National Cancer Institute, National Institutes of Health, Department of Health and Human Services Grants R01 CA083688 and CA132740 (to P.S.).

Keywords

Cell cycle
Ciliogenesis
Cyclins
Epithelial differentiation
miR-34

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.1702914114

Cite this

Otto, T., Candido, S. V., Pilarz, M. S., Sicinska, E., Bronson, R. T., Bowden, M., Lachowicz, I. A., Mulry, K., Fassl, A., Han, R. C., Jecrois, E. S., & Sicinski, P. (2017). Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit. Proceedings of the National Academy of Sciences of the United States of America, 114(40), 10660-10665. https://doi.org/10.1073/pnas.1702914114

@article{78c56136d70343d9a999a3e0cfc8b196,

title = "Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit",

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",

author = "Tobias Otto and Candido, \{Sheyla V.\} and Pilarz, \{Mary S.\} and Ewa Sicinska and Bronson, \{Roderick T.\} and Michaela Bowden and Lachowicz, \{Iga A.\} and Kristin Mulry and Anne Fassl and Han, \{Richard C.\} and Jecrois, \{Emmanuelle S.\} and Piotr Sicinski",

year = "2017",

month = oct,

day = "3",

doi = "10.1073/pnas.1702914114",

language = "English (US)",

volume = "114",

pages = "10660--10665",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "40",

}

Otto, T, Candido, SV, Pilarz, MS, Sicinska, E, Bronson, RT, Bowden, M, Lachowicz, IA, Mulry, K, Fassl, A, Han, RC, Jecrois, ES & Sicinski, P 2017, 'Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 40, pp. 10660-10665. https://doi.org/10.1073/pnas.1702914114

TY - JOUR

T1 - Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit

AU - Otto, Tobias

AU - Candido, Sheyla V.

AU - Pilarz, Mary S.

AU - Sicinska, Ewa

AU - Bronson, Roderick T.

AU - Bowden, Michaela

AU - Lachowicz, Iga A.

AU - Mulry, Kristin

AU - Fassl, Anne

AU - Han, Richard C.

AU - Jecrois, Emmanuelle S.

AU - Sicinski, Piotr

PY - 2017/10/3

Y1 - 2017/10/3

N2 - 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.

AB - 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.

KW - Cell cycle

KW - Ciliogenesis

KW - Cyclins

KW - Epithelial differentiation

KW - miR-34

UR - http://www.scopus.com/inward/record.url?scp=85030265282&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030265282&partnerID=8YFLogxK

U2 - 10.1073/pnas.1702914114

DO - 10.1073/pnas.1702914114

M3 - Article

C2 - 28923932

AN - SCOPUS:85030265282

SN - 0027-8424

VL - 114

SP - 10660

EP - 10665

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 40

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this