title: C-terminal-binding protein interacting protein binds directly to adenovirus early region 1A through its N-terminal region and conserved region 3.
abstract: C-terminal-binding protein interacting protein (CtIP) was first isolated as a binding partner of C-terminal-binding protein (CtBP). It is considered to contribute to the transcriptional repression and cell cycle regulatory properties of the retinoblastoma (Rb) family of proteins and to have a role in the cellular response to DNA damage. Here, we have shown that CtIP is a novel target for the adenovirus oncoprotein early region 1A (AdE1A). AdE1A associates with CtIP in both Ad5E1-transformed cells and Ad5-infected cells and binds directly in glutathione-S-transferase pull-down assays. Two binding sites have been mapped on Ad5E1A - the N-terminal alpha-helical region (residues 1-30) and conserved region 3 (CR3) - the transcriptional activation domain. CtIP can bind AdE1A and CtBP independently, raising the possibility that ternary complexes exist in Ad-transformed and -infected cells. Significantly, reduction of CtIP expression with small interfering RNAs results in reduction of the ability of a Gal4 DNA-binding domain-CR3 construct to transactivate a Gal 4-responsive luciferase reporter and this effect is reversed by reduction of CtBP expression. Therefore, in this model, CtIP acts as a transcriptional co-activator of AdE1A when dissociated from CtBP, through the action of AdE1A. These data are consistent with observations that CtIP expression is induced by AdE1A during viral infection and that reduction of CtIP expression with RNA interference can retard virus replication. In addition, AdE1A causes disruption of the CtIP/Rb complex during viral infection by its interaction with CtIP, possibly contributing to transcriptional derepression.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, The Medical School, University of Birmingham, Birmingham, UK.
authors.forename: R K
authors.initials: RK
authors.lastname: Bruton
authors.forename: M
authors.initials: M
authors.lastname: Rasti
authors.forename: K L
authors.initials: KL
authors.lastname: Mapp
authors.forename: N
authors.initials: N
authors.lastname: Young
authors.forename: R Z
authors.initials: RZ
authors.lastname: Carter
authors.forename: I A
authors.initials: IA
authors.lastname: Abramowicz
authors.forename: G G
authors.initials: GG
authors.lastname: Sedgwick
authors.forename: D F
authors.initials: DF
authors.lastname: Onion
authors.forename: M
authors.initials: M
authors.lastname: Shuen
authors.forename: J S
authors.initials: JS
authors.lastname: Mymryk
authors.forename: A S
authors.initials: AS
authors.lastname: Turnell
authors.forename: R J A
authors.initials: RJ
authors.lastname: Grand
mesh_terms: D000256:Adenoviridae / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000258:Adenovirus Infections, Human / Q000235:genetics / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000378:metabolism; D015533:Transcriptional Activation; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human