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.

Adenovirus E1A Targets the DREF Nuclear Factor To Regulate Virus Gene Expression, DNA Replication, and Growth

“…2B). The ability to bind proteins via multiple regions is a property of E1A that has been previously noted for multiple targets (2,(39)(40)(41). Although we are unsure of the consequences of DREF binding to E1A via CR3, the CR4-mediated interaction is required for the ability of E1A to enhance DREF SUMOylation (Fig.…”

“…By altering the function of hub proteins in cellular networks, E1A serves as a "hub detector" by which key cellular regulators can be identified. The interaction of E1A with mammalian regulatory proteins has been heavily exploited to elucidate the molecular basis by which these hub proteins control cellular processes (1)(2)(3)(4)(5). Studying the interactions of E1A with recently identified binding proteins provides a unique opportunity to investigate critical mechanisms controlling mammalian transcription, growth, and differentiation.…”

“…he interaction of the adenovirus early 1A (E1A) proteins with mammalian regulatory factors has been heavily exploited to elucidate the molecular basis by which they control cellular processes (1)(2)(3)(4)(5). Studying the interactions of E1A with new cellular targets provides an exciting opportunity to identify and dissect critical mechanisms controlling mammalian transcription, growth, and differentiation, as well as to identify novel viral regulatory mechanisms.…”

Cell cycle S phase markers are expressed in cerebral neuron nuclei of cats infected by the Feline Panleukopenia Virus

“…24 The E1A protein from adenoviruses also displays this property. 26,27 A potential co-infection with an adenovirus was investigated by PCR analysis using cerebellumextracted DNA from the 4 cats with extracerebellar FPV protein expression, but no evidence of an adenoviral co-infection was found. Herpes viruses interfere with the E2F transcription factors through different mechanisms, either by retinoblastoma protein phosphorylation and E2F dependent genes expression, or by the production of viral retinoblastoma-inactivating proteins.…”

“…[24][25][26][27] Nested PCRs using either pan herpes (215-235 bp products from the viral DNA polymerase) or pan adeno primers (324 bp product from the viral DNA polymerase gene) were conducted on cats 7, 10-12 ( Fig. 2).…”