title: Adenovirus E1A directly targets the E2F/DP-1 complex.
abstract: Deregulation of the cell cycle is of paramount importance during adenovirus infection. Adenovirus normally infects quiescent cells and must initiate the cell cycle in order to propagate itself. The pRb family of proteins controls entry into the cell cycle by interacting with and repressing transcriptional activation by the E2F transcription factors. The viral E1A proteins indirectly activate E2F-dependent transcription and cell cycle entry, in part, by interacting with pRb and family members to free the E2Fs. We report here that an E1A 13S isoform can unexpectedly activate E2F-responsive gene expression independently of binding to the pRb family of proteins. We demonstrate that E1A binds to E2F/DP-1 complexes through a direct interaction with DP-1. E1A appears to utilize this binding to recruit itself to E2F-regulated promoters, and this allows the E1A 13S protein, but not the E1A 12S protein, to activate transcription independently of interaction with pRb. Importantly, expression of E1A 13S, but not E1A 12S, led to significant enhancement of E2F4 occupancy of E2F sites of two E2F-regulated promoters. These observations identify a novel mechanism by which adenovirus deregulates the cell cycle and suggest that E1A 13S may selectively activate a subset of E2F-regulated cellular genes during infection.
authors.affiliation: Department of Pathology and Molecular Medicine, MG DeGroote Institute for Infectious Disease Research, McMaster University, MDCL 4077, 1280 Main Street West, Hamilton, ON, Canada L8S 4K1. peter.pelka@gmail.com
authors.forename: Peter
authors.initials: P
authors.lastname: Pelka
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Miller
authors.forename: Matthew
authors.initials: M
authors.lastname: Cecchini
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: Yousef
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Bowdish
authors.forename: Fred
authors.initials: F
authors.lastname: Dick
authors.forename: Peter
authors.initials: P
authors.lastname: Whyte
authors.forename: Joe S
authors.initials: JS
authors.lastname: Mymryk
mesh_terms: D000256:Adenoviridae / Q000472:pathogenicity*; D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000378:metabolism*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D011485:Protein Binding; D025941:Protein Interaction Mapping; D050680:Transcription Factor DP1 / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D050684:E2F Transcription Factors; C493735:TFDP1 protein, human; D050680:Transcription Factor DP1