High levels of oncomiR‐21 contribute to the senescence‐induced growth arrest in normal human cells and its knock‐down increases the replicative lifespan
Summary Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double‐edged role as tumour suppressor and promoter. Importan...
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| Published in | Aging cell Vol. 12; no. 3; pp. 446 - 458 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
John Wiley & Sons, Inc
01.06.2013
Blackwell Publishing Ltd |
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| Online Access | Get full text |
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| Abstract | Summary
Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double‐edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age‐associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa‐miR‐23a, hsa‐miR‐23b, hsa‐miR‐24, hsa‐miR‐27a, hsa‐miR‐29a, hsa‐miR‐31, hsa‐miR‐100, hsa‐miR‐193a, hsa‐miR‐221, hsa‐miR‐222 and hsa‐let‐7i are consistently up‐regulated in replicatively senescent cells. Surprisingly, also miR‐21 was found up‐regulated by replicative and stress‐induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR‐21 resulted in lower angiogenesis, and less cell proliferation mirrored by up‐regulation of p21CIP1 and down‐regulation of CDK2. These two cell‐cycle regulators are indirectly regulated by miR‐21 via its validated direct targets NFIB (Nuclear factor 1 B‐type), a transcriptional inhibitor of p21CIP1, and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock‐down of either NFIB or CDC25A shows a phenocopy of over‐expressing miR‐21 in regard to cell‐cycle arrest. Finally, miR‐21 over‐epxression reduces the replicative lifespan, while stable knock‐down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR‐21 is the first miRNA that upon its knock‐down extends the replicative lifespan of normal human cells. |
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| AbstractList | Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double-edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age-associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa-miR-23a, hsa-miR-23b, hsa-miR-24, hsa-miR-27a, hsa-miR-29a, hsa-miR-31, hsa-miR-100, hsa-miR-193a, hsa-miR-221, hsa-miR-222 and hsa-let-7i are consistently up-regulated in replicatively senescent cells. Surprisingly, also miR-21 was found up-regulated by replicative and stress-induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR-21 resulted in lower angiogenesis, and less cell proliferation mirrored by up-regulation of p21[sup.CIP1] and down-regulation of CDK2. These two cell-cycle regulators are indirectly regulated by miR-21 via its validated direct targets NFIB (Nuclear factor 1 B-type), a transcriptional inhibitor of p21[sup.CIP] [sup.1], and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock-down of either NFIB or CDC25A shows a phenocopy of over-expressing miR-21 in regard to cell-cycle arrest. Finally, miR-21 over-epxression reduces the replicative lifespan, while stable knock-down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR-21 is the first miRNA that upon its knock-down extends the replicative lifespan of normal human cells. Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo , their effect on their microenvironment and its double-edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age-associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa-miR-23a, hsa-miR-23b, hsa-miR-24, hsa-miR-27a, hsa-miR-29a, hsa-miR-31, hsa-miR-100, hsa-miR-193a, hsa-miR-221, hsa-miR-222 and hsa-let-7i are consistently up-regulated in replicatively senescent cells. Surprisingly, also miR-21 was found up-regulated by replicative and stress-induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR-21 resulted in lower angiogenesis, and less cell proliferation mirrored by up-regulation of p21 CIP1 and down-regulation of CDK2. These two cell-cycle regulators are indirectly regulated by miR-21 via its validated direct targets NFIB (Nuclear factor 1 B-type), a transcriptional inhibitor of p21 CIP 1 , and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock-down of either NFIB or CDC25A shows a phenocopy of over-expressing miR-21 in regard to cell-cycle arrest. Finally, miR-21 over-epxression reduces the replicative lifespan, while stable knock-down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR-21 is the first miRNA that upon its knock-down extends the replicative lifespan of normal human cells. Summary Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double‐edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age‐associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa‐miR‐23a, hsa‐miR‐23b, hsa‐miR‐24, hsa‐miR‐27a, hsa‐miR‐29a, hsa‐miR‐31, hsa‐miR‐100, hsa‐miR‐193a, hsa‐miR‐221, hsa‐miR‐222 and hsa‐let‐7i are consistently up‐regulated in replicatively senescent cells. Surprisingly, also miR‐21 was found up‐regulated by replicative and stress‐induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR‐21 resulted in lower angiogenesis, and less cell proliferation mirrored by up‐regulation of p21CIP1 and down‐regulation of CDK2. These two cell‐cycle regulators are indirectly regulated by miR‐21 via its validated direct targets NFIB (Nuclear factor 1 B‐type), a transcriptional inhibitor of p21CIP1, and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock‐down of either NFIB or CDC25A shows a phenocopy of over‐expressing miR‐21 in regard to cell‐cycle arrest. Finally, miR‐21 over‐epxression reduces the replicative lifespan, while stable knock‐down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR‐21 is the first miRNA that upon its knock‐down extends the replicative lifespan of normal human cells. Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double‐edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age‐associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa‐miR‐23a, hsa‐miR‐23b, hsa‐miR‐24, hsa‐miR‐27a, hsa‐miR‐29a, hsa‐miR‐31, hsa‐miR‐100, hsa‐miR‐193a, hsa‐miR‐221, hsa‐miR‐222 and hsa‐let‐7i are consistently up‐regulated in replicatively senescent cells. Surprisingly, also miR‐21 was found up‐regulated by replicative and stress‐induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR‐21 resulted in lower angiogenesis, and less cell proliferation mirrored by up‐regulation of p21CIP1 and down‐regulation of CDK2. These two cell‐cycle regulators are indirectly regulated by miR‐21 via its validated direct targets NFIB (Nuclear factor 1 B‐type), a transcriptional inhibitor of p21CIP1, and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock‐down of either NFIB or CDC25A shows a phenocopy of over‐expressing miR‐21 in regard to cell‐cycle arrest. Finally, miR‐21 over‐epxression reduces the replicative lifespan, while stable knock‐down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR‐21 is the first miRNA that upon its knock‐down extends the replicative lifespan of normal human cells. Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double-edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age-associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa-miR-23a, hsa-miR-23b, hsa-miR-24, hsa-miR-27a, hsa-miR-29a, hsa-miR-31, hsa-miR-100, hsa-miR-193a, hsa-miR-221, hsa-miR-222 and hsa-let-7i are consistently up-regulated in replicatively senescent cells. Surprisingly, also miR-21 was found up-regulated by replicative and stress-induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR-21 resulted in lower angiogenesis, and less cell proliferation mirrored by up-regulation of p21(CIP1) and down-regulation of CDK2. These two cell-cycle regulators are indirectly regulated by miR-21 via its validated direct targets NFIB (Nuclear factor 1 B-type), a transcriptional inhibitor of p21(CIP) (1) , and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock-down of either NFIB or CDC25A shows a phenocopy of over-expressing miR-21 in regard to cell-cycle arrest. Finally, miR-21 over-epxression reduces the replicative lifespan, while stable knock-down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR-21 is the first miRNA that upon its knock-down extends the replicative lifespan of normal human cells. Summary Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double-edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age-associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa-miR-23a, hsa-miR-23b, hsa-miR-24, hsa-miR-27a, hsa-miR-29a, hsa-miR-31, hsa-miR-100, hsa-miR-193a, hsa-miR-221, hsa-miR-222 and hsa-let-7i are consistently up-regulated in replicatively senescent cells. Surprisingly, also miR-21 was found up-regulated by replicative and stress-induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR-21 resulted in lower angiogenesis, and less cell proliferation mirrored by up-regulation of p21CIP1 and down-regulation of CDK2. These two cell-cycle regulators are indirectly regulated by miR-21 via its validated direct targets NFIB (Nuclear factor 1 B-type), a transcriptional inhibitor of p21CIP1, and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock-down of either NFIB or CDC25A shows a phenocopy of over-expressing miR-21 in regard to cell-cycle arrest. Finally, miR-21 over-epxression reduces the replicative lifespan, while stable knock-down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR-21 is the first miRNA that upon its knock-down extends the replicative lifespan of normal human cells. [PUBLICATION ABSTRACT] |
| Audience | Academic |
| Author | Preschitz‐Kammerhofer, Barbara Grillari, Johannes Monteforte, Rossella Grillari‐Voglauer, Regina Tschachler, Erwin Wieser, Matthias Chang, Martina W.‐F. Kühnel, Harald Dellago, Hanna Hackl, Matthias Fortschegger, Klaus Scheideler, Marcel Schreiner, Carina Schosserer, Markus Gruber, Florian Terlecki‐Zaniewicz, Lucia |
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| Copyright | 2013 John Wiley & Sons Ltd and the Anatomical Society 2013 John Wiley & Sons Ltd and the Anatomical Society. COPYRIGHT 2013 John Wiley & Sons, Inc. 2013. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2013 John Wiley & Sons Ltd and the Anatomical Society 2013 |
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Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the... Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of... Summary Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the... |
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| SubjectTerms | Aging Angiogenesis Apoptosis cdc25 Phosphatases - genetics CDC25A CDK2 Cell Proliferation Cells Cells, Cultured Cellular biology cellular senescence Cellular Senescence - genetics Cyclin-dependent kinase 2 Cyclin-Dependent Kinase 2 - biosynthesis Cyclin-Dependent Kinase 2 - metabolism Cyclin-dependent kinase inhibitor p21 Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Dephosphorylation Down-Regulation Endothelial cells Fibroblasts Genotype & phenotype Growth Human Umbilical Vein Endothelial Cells - metabolism Humans hyperoncogenic signal Life span Microenvironments MicroRNA MicroRNAs - genetics MicroRNAs - metabolism miRNA miR‐21 Morphology Neovascularization, Physiologic - genetics NFI Transcription Factors - genetics NFI Transcription Factors - metabolism NFIB Original Oxidative stress p21 Proteins RNA Interference RNA, Small Interfering Senescence Statistical analysis Transcription Transfection Tumor suppressor genes Tumors Up-Regulation |
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| Title | High levels of oncomiR‐21 contribute to the senescence‐induced growth arrest in normal human cells and its knock‐down increases the replicative lifespan |
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