title: Conserved regulation of p53 network dosage by microRNA-125b occurs through evolving miRNA-target gene pairs.
abstract: MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain- and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA-target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis.
authors.affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Minh T N
authors.initials: MT
authors.lastname: Le
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
authors.forename: Swea Ling
authors.initials: SL
authors.lastname: Khaw
authors.forename: Lingzi
authors.initials: L
authors.lastname: Chin
authors.forename: Cathleen
authors.initials: C
authors.lastname: Teh
authors.forename: Junliang
authors.initials: J
authors.lastname: Tay
authors.forename: Elizabeth
authors.initials: E
authors.lastname: O'Day
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korzh
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.forename: Ashish
authors.initials: A
authors.lastname: Lal
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
mesh_terms: D020413:3' Untranslated Regions; D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008845:Microinjections; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015027:Zebrafish
chemical_list: D020413:3' Untranslated Regions; C531888:MIRN125 microRNA, human; C569474:MIRN125 microRNA, zebrafish; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D016159:Tumor Suppressor Protein p53