title: Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells.
abstract: Inactivation of the retinoblastoma tumor suppressor (pRb) is a common oncogenic event that alters the expression of genes important for cell cycle progression, senescence, and apoptosis. However, in many contexts, the properties of pRb-deficient cells are similar to wild-type cells suggesting there may be processes that counterbalance the transcriptional changes associated with pRb inactivation. Therefore, we have looked for sets of evolutionary conserved, functionally related genes that are direct targets of pRb/E2F proteins. We show that the expression of NANOS, a key facilitator of the Pumilio (PUM) post-transcriptional repressor complex, is directly repressed by pRb/E2F in flies and humans. In both species, NANOS expression increases following inactivation of pRb/RBF1 and becomes important for tissue homeostasis. By analyzing datasets from normal retinal tissue and pRb-null retinoblastomas, we find a strong enrichment for putative PUM substrates among genes de-regulated in tumors. These include pro-apoptotic genes that are transcriptionally down-regulated upon pRb loss, and we characterize two such candidates, MAP2K3 and MAP3K1, as direct PUM substrates. Our data suggest that NANOS increases in importance in pRb-deficient cells and helps to maintain homeostasis by repressing the translation of transcripts containing PUM Regulatory Elements (PRE).
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School Laboratory of Molecular Oncology, Charlestown, MA, USA.
authors.forename: Wayne O
authors.initials: WO
authors.lastname: Miles
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School Laboratory of Molecular Oncology, Charlestown, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Korenjak
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Lyra M
authors.initials: LM
authors.lastname: Griffiths
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School Laboratory of Molecular Oncology, Charlestown, MA, USA dyson@helix.mgh.harvard.edu.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D029721:Drosophila Proteins; D050684:E2F Transcription Factors; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C515170:NANOS1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016160:Retinoblastoma Protein; C070574:nos protein, Drosophila; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human
keywords: Nanos; Pumilio; pRb; post‐transcriptional gene regulation; stress response
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