Abstract
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.
Highlights
Small DNA viruses such as adenovirus, papilloma virus, and SV-40 rely on the host cell for many of the steps needed for their own propagation
Because associated virus-2 (AAV) inhibits the oncogenic potentials of such a wide variety of DNA tumor viruses, we investigated whether AAV interferes with the disruption of the pRB-E2F-1 complex, which is the hallmark of all DNA tumor virus-mediated cell proliferation
Because AAV inhibits the adenovirus and other DNA virus-mediated cellular DNA replication and cell proliferation, we examined the expression of E2F-1 protein in the presence or absence of AAV in adenovirus-infected human cells
Summary
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. The transforming potentials of adenovirus (Ad) [4, 6, 7] and other DNA tumor viruses such as simian virus 40 (SV40) (8 –12) and human papilloma virus [13, 14] are inhibited by AAV These tumor-suppressive and antiproliferative properties have been mapped to the left half of the AAV genome, which codes for the multifunctional regulatory protein Rep78 [15, 16]. This report shows that AAV Rep acts on E2F-1 at transcription as well as pRB interaction levels to decrease E2F-1 activity and provides a definite molecular mechanism for the antioncogenic property of AAV Rep
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