Dual level inhibition of E2F-1 activity by adeno-associated virus Rep78.
E2F-1, a major cellular transcription factor, plays a pivotal role in regulating the cell cycle. The activity of E2F-1 is negatively regulated by its interaction with retinoblastoma protein (pRB), and disruption of the pRB-E2F-1 complex, a hallmark of cellular transformation by DNA tumor viruses, leads to cell proliferation. Adeno-associated virus-2 (AAV) is known to have onco-suppressive properties against DNA tumor viruses. Here we provide, for the first time, the molecular basis for antioncogenic activity of AAV. Rep78, a major regulatory protein of AAV, interacts at the protein level with E2F-1 and stabilizes the pRB-E2F-1 complex. At the DNA level, Rep78 binds to a putative site on the E2F-1 promoter and down-regulates the adenovirus-induced E2F-1 transcription. This dual level of Rep78 activity leads to decreased cellular levels of free E2F-1, leading to its onco-suppressive properties.
Batchu
R B
RB
Central Arkansas Veterans Health Care System and Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Shammas
M A
MA
Wang
J Y
JY
Munshi
N C
NC
D017500:Adenovirus E1A Proteins / Q000502:physiology; D001483:Base Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D000229:Dependovirus / Q000502:physiology; D015536:Down-Regulation; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014764:Viral Proteins / Q000502:physiology*
D017500:Adenovirus E1A Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D014764:Viral Proteins; C068734:rep proteins, Adeno-associated virus 2