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Published on: April 24, 2021
MicroRNAs 221 and 222 bypass quiescence and compromise cell survival
Ricardo Medina1, Sayyed K Zaidi, Chang-Gong Liu
1Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Abstract:
MicroRNAs (miRNA) have tumor suppressive and oncogenic potential in human cancer, but whether and how miRNAs control cell cycle progression is not understood. To address this question, we carried out a comprehensive analysis of miRNA expression during serum stimulation of quiescent human cells. Time course analyses revealed that four miRNAs are up-regulated and >100 miRNAs are down-regulated, as cells progress beyond the G(1)-S phase transition. We analyzed the function of two up-regulated miRNAs (miR-221 and miR-222) that are both predicted to target the cell growth suppressive cyclin-dependent kinase inhibitors p27 and p57. Our results show that miR-221 and miR-222 both directly target the 3' untranslated regions of p27 and p57 mRNAs to reduce reporter gene expression, as well as diminish p27 and p57 protein levels. Functional studies show that miR-221 and miR-222 prevent quiescence when elevated during growth factor deprivation and induce precocious S-phase entry, thereby triggering cell death. Thus, the physiologic up-regulation of miR-221 and miR-222 is tightly linked to a cell cycle checkpoint that ensures cell survival by coordinating competency for initiation of S phase with growth factor signaling pathways that stimulate cell proliferation.
Insights
MicroRNAs (miRNAs) regulate the cell cycle. Specifically, miR-221 and miR-222 promote cell cycle progression and survival by targeting cell cycle inhibitors p27 and p57.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- MicroRNAs (miRNAs) play dual roles in human cancer, acting as tumor suppressors or oncogenes.
- The precise mechanisms by which miRNAs regulate cell cycle progression remain largely unknown.
Purpose of the Study:
- To investigate the role of miRNAs in controlling cell cycle progression during human cell serum stimulation.
- To elucidate the function of specific miRNAs, namely miR-221 and miR-222, in regulating cell cycle transitions.
Main Methods:
- Comprehensive analysis of miRNA expression during serum stimulation of quiescent human cells.
- Functional studies involving reporter gene assays and protein level analysis to assess the targeting of p27 and p57 by miR-221 and miR-222.
- Investigation of the impact of these miRNAs on cell quiescence, S-phase entry, and cell death.
Main Results:
- Over 100 miRNAs were down-regulated, while four were up-regulated as cells transitioned beyond the G(1)-S phase.
- miR-221 and miR-222 were found to directly target the 3' untranslated regions of p27 and p57 mRNAs, reducing their expression and protein levels.
- Elevated miR-221 and miR-222 levels prevented quiescence, induced premature S-phase entry, and triggered cell death.
Conclusions:
- Physiologic up-regulation of miR-221 and miR-222 is linked to a cell cycle checkpoint.
- These miRNAs coordinate S-phase entry competency with growth factor signaling to ensure cell survival.
- miR-221 and miR-222 play a critical role in regulating cell proliferation and preventing uncontrolled cell growth.
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