Abstract
The conserved regions (CR) of adenoviral E1A had been shown to be necessary for disruption of pRb-E2F transcription factor complexes and induction of the S phase. Here we constructed a mutant adenoviral E1A with Rb-binding ability absent (E1A 30-60aa and 120-127aa deletion, mE1A) and investigated its antitumor capacities in vitro and in vivo. The mE1A suppressed the viability of tumor cells as efficiently as the wild type E1A, and there was no cytotoxic effect on normal cells. Although the mE1A arrested tumor cell cycle with the same manner as E1A, the former played a different role on cell cycle regulation compared with E1A in normal cells, which might contribute to its selective antitumor activity. E1A and mE1A had accumulated inactive p53, decreased the expression of mdm2, Cdkn1a (also named p21), increased p21's nuclear distribution and induced tumor cell apoptosis in a p53-indenpent manner. Further, E1A or mE1A significantly suppressed tumor growth in subcutaneous hepatocellular carcinoma xenograft models. Especially, tumor-bearing mice treated with mE1A had higher survival rate than those treated with E1A. Our data demonstrated that mutant adenoviral E1A significantly induced tumor cell apoptosis in a p53-indenpednt manner and had selective tumor suppressing ability. The observations of adenoviral E1A mutant had provided a novel mechanism for E1A's complex activities during infection.
Highlights
The human adenoviral early region 1A (E1A) is the first viral protein to be expressed following infection [1]
We examined the express of E1A protein mediated by adenovirus in HepG2 cancer cells using western blot analysis
These results suggested that mutant E1A, unlike wild type E1A, had lost the ability to bind to Rb protein
Summary
The human adenoviral early region 1A (E1A) is the first viral protein to be expressed following infection [1]. It was originally considered as an oncogene of the adenovirus genome [2]. E1A is identified and associated with multiple anti-cancer activities by modulating host cell transcriptional machinery [3,4,5,6,7]. The clinical trials with E1A/ liposome gene therapy for breast, ovarian and head/ neck cancers had been conducted [10,11,12]. The molecular mechanism mediated by adenoviral E1A for this tumor inhibition is not yet clearly described
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