title: FMN2 is a novel regulator of the cyclin-dependent kinase inhibitor p21.
abstract: We have identified the human FMN2 gene as a novel target regulated by induction of p14ARF and by multiple other stress responses, including DNA damage and hypoxia, which have in common activation of cell cycle arrest. We showed that increased expression of the FMN2 gene following p14ARF induction is caused, at the transcriptional level, by relief of repression by RelA and E2F1, which, under non-induced conditions, bind the FMN2 promoter. Increased FMN2 protein levels promote cell cycle arrest by inhibiting the degradation of p21, and our data show that control of p21 stability is a key part of the mechanism that regulates p21 induction. Consistent with this model, we have shown that transient expression of exogenous FMN2 protein alone is sufficient to increase p21 protein levels in cells, without altering p21 mRNA levels. Here, we provide additional evidence for the role of the N terminus of FMN2 as being the important domain required for p21 stability. In addition, we also investigate the role of RelA's threonine 505 residue in the control of FMN2. Our results identify FMN2 as a crucial protein involved in the control of p21.
authors.affiliation: Centre for Gene Regulation and Expression; College of Life Sciences; University of Dundee; Dundee, Scotland, UK.
authors.forename: Kayo
authors.initials: K
authors.lastname: Yamada
authors.forename: Motoharu
authors.initials: M
authors.lastname: Ono
authors.forename: Dalila
authors.initials: D
authors.lastname: Bensaddek
authors.forename: Angus I
authors.initials: AI
authors.lastname: Lamond
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D000080865:Formins; D005786:Gene Expression Regulation; D006801:Humans; D008840:Microfilament Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C587953:Fmn2 protein, human; D000080865:Formins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C498143:RELA protein, human; D051996:Transcription Factor RelA
keywords: Cancer; Cell Cycle; DNA damage; FMN2; hypoxia; p14ARF; p21; p53