Multiple E2F-induced microRNAs prevent replicative stress in response to mitogenic signaling.
Transcription of microRNAs (miRNAs) is thought to be regulated similarly to that of protein-coding genes. However, how miRNAs are regulated during the cell division cycle is not well understood. We have analyzed the transcription profiles of miRNAs in response to mitogenic stimulation in primary fibroblasts. About 33% of the miRNAs expressed in these cells are induced upon exit from quiescence. Many of these miRNAs are specifically induced by E2F1 or E2F3 during the G(1)/S transition and are repressed in E2F1/3-knockout cells. At least four miRNA clusters, let-7a-d, let-7i, mir-15b-16-2, and mir-106b-25, are direct targets of E2F1 and E2F3 during G(1)/S and are repressed in E2F1/3-null cells. Interestingly, these miRNAs do not contribute to E2F-dependent entry into S phase but rather inhibit the G(1)/S transition by targeting multiple cell cycle regulators and E2F targets. In fact, E2F1 expression results in a significant increase in S-phase entry and DNA damage in the absence of these microRNAs. Thus, E2F-induced miRNAs contribute to limiting the cellular responses to E2F activation, thus preventing replicative stress. Given the known function of E2F of inducing other oncogenic miRNAs, control of miRNAs by E2F is likely to play multiple roles in cell proliferation and in proliferative diseases such as cancer.
Bueno
María J
MJ
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Gómez de Cedrón
Marta
M
Laresgoiti
Usua
U
Fernández-Piqueras
José
J
Zubiaga
Ana M
AM
Malumbres
Marcos
M
D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D050684:E2F Transcription Factors / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
D018797:Cell Cycle Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D035683:MicroRNAs; D008934:Mitogens
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