Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit
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 p...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 40; pp. 10660 - 10665 |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
03.10.2017
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8424 1091-6490 1091-6490 |
| DOI | 10.1073/pnas.1702914114 |
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| 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. |
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| AbstractList | The interplay between microRNAs and the cell-cycle machinery in vivo remains poorly understood. Here we report that the microRNA family miR-34/449 plays an essential and rate-limiting role in repressing cell-cycle proteins and enforcing cell-cycle exit during epithelial cell differentiation. We demonstrate that genetic ablation of the entire miR-34/449 family leads to derepression of cell cycle-promoting proteins in differentiating epithelial cells, thereby preventing their timely cell-cycle exit. This, in turn, impairs epithelial ciliation and leads to profound developmental defects. Hence, this study describes a function of the miR-34/449 family in linking cell proliferation and differentiation.
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. 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. 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.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. |
| Author | Mulry, Kristin Sicinski, Piotr Fassl, Anne Han, Richard C. Pilarz, Mary S. Candido, Sheyla V. Jecrois, Emmanuelle S. Sicinska, Ewa Otto, Tobias Bronson, Roderick T. Bowden, Michaela Lachowicz, Iga A. |
| Author_xml | – sequence: 1 givenname: Tobias surname: Otto fullname: Otto, Tobias organization: Department of Genetics, Harvard Medical School, Boston, MA 02115 – sequence: 2 givenname: Sheyla V. surname: Candido fullname: Candido, Sheyla V. organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 – sequence: 3 givenname: Mary S. surname: Pilarz fullname: Pilarz, Mary S. organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 – sequence: 4 givenname: Ewa surname: Sicinska fullname: Sicinska, Ewa organization: Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215 – sequence: 5 givenname: Roderick T. surname: Bronson fullname: Bronson, Roderick T. organization: Rodent Histopathology Core, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115 – sequence: 6 givenname: Michaela surname: Bowden fullname: Bowden, Michaela organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 – sequence: 7 givenname: Iga A. surname: Lachowicz fullname: Lachowicz, Iga A. organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 – sequence: 8 givenname: Kristin surname: Mulry fullname: Mulry, Kristin organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 – sequence: 9 givenname: Anne surname: Fassl fullname: Fassl, Anne organization: Department of Genetics, Harvard Medical School, Boston, MA 02115 – sequence: 10 givenname: Richard C. surname: Han fullname: Han, Richard C. organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 – sequence: 11 givenname: Emmanuelle S. surname: Jecrois fullname: Jecrois, Emmanuelle S. organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 – sequence: 12 givenname: Piotr surname: Sicinski fullname: Sicinski, Piotr organization: Department of Genetics, Harvard Medical School, Boston, MA 02115 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28923932$$D View this record in MEDLINE/PubMed |
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| Copyright | Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles Copyright National Academy of Sciences Oct 3, 2017 |
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| Keywords | epithelial differentiation cell cycle ciliogenesis miR-34 cyclins |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Author contributions: T.O. and P.S. designed research; T.O., S.V.C., M.S.P., E.S., M.B., I.A.L., K.M., A.F., R.C.H., and E.S.J. performed research; T.O., E.S., R.T.B., M.B., and P.S. analyzed data; and T.O. and P.S. wrote the paper. 1Present address: Department of Internal Medicine III, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen 52074, Germany. Edited by Terry L. Orr-Weaver, Whitehead Institute, Cambridge, MA, and approved August 24, 2017 (received for review February 22, 2017) |
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| Snippet | MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of... The interplay between microRNAs and the cell-cycle machinery in vivo remains poorly understood. Here we report that the microRNA family miR-34/449 plays an... |
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| SubjectTerms | Biological activity Biological Sciences Cell cycle Cell differentiation Derepression Differentiation (biology) Epithelial cells Epithelium Fallopian tube Gene expression Genes Infertility Machinery and equipment MicroRNAs miRNA Proteins Respiratory tract diseases Rodents |
| Title | Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit |
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