Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B.

Abstract

Transformation of primary rodent cells by the adenovirus EIA and E1B oncogenes is a two-step process, where E1A-dependent induction of proliferation is coupled to E1B-dependent suppression of programmed cell death {apoptosis). The E1B gene encodes two distinct transforming proteins, the 19K and 55K proteins, both of which independently cooperate with EIA. E1B 19K or 55K protein, or the human Bcl-2 protein, functions to suppress apoptosis and thereby permits transformation with E1A. The E1B 55K protein blocks p53 tumor suppressor protein function, indicating that p53 may mediate apoptosis by E1A. In the mutant conformation, p53 blocked induction of apoptosis by E1A and efficiently cooperated with E1A to transform primary cells. When p53 was returned to the wild-type conformation, E1A+p53 transformants underwent cell death by apoptosis. This induction of apoptosis by conformational shift of p53 from the mutant to the wild-type form was inhibited by expression of the E1B 19K protein. Thus, the p53 protein may function as a tumor suppressor by initiating a cell suicide response to deregulation of growth control by EIA. E1B 19K and 55K proteins provide separate mechanisms that disable the cell suicide pathway of p53.

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

“…In this context, the adenoviral E1b-19kD protein is likely to be of great importance, as it is know to be a very potent inhibitor of p53-dependent apoptosis. 41,42 Deletion of the E1b-19kD gene of a replicating adenovirus has been shown to improve cancer cell killing and viral spread in vitro and in vivo. 20,35,43 Such a deletion should be especially effective in the context of p53 expression, as apoptosis is a major mechanism by which p53 exerts its tumor suppressor function.…”

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

“…Our identification of astrocytoma cases with high immunostaining scores, in the absence of mutations in coding sequences of the p53 gene, suggests that p53 may act through downstream mechanisms that are distinct from purely tumour-suppressive functions in its native form, or as a dominant-negative regulator in mutant or oncogenic forms. Normal cellular proteins that bind to p53 in a manner similar to viral oncoproteins were identified and found to be potential oncogenes (Scheffner et al, 1990;Bargonetti et al, 1991;Debbas and White, 1993;Nees et al, 2001;Cobbs et al, 2003;Dai et al, 2003;Calogero et al, 2004). Proteins implicated in cell cycle regulation may serve as downstream effectors of p53 function (Dulic et al, 1994;Agarwal et al, 1995;de Toledo et al, 1998;Skomedal et al, 1999;Ghimenti et al, 2003).…”

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

“…First, E1B55K binds to the amino terminus of p53, thus inhibiting p53 transactivation. [6][7][8][9] Second, E1B55K, together with the Ad E4orf6 protein, degrades p53 protein in Ad-infected cells. [10][11][12] The E1B19K protein is a functional homologue of the antiapoptotic cellular protein, Bcl-2.…”

“…It is thought that E1B19K prevents E1A-induced apoptosis by interfering with the actions of the proapoptotic proteins, Bak and Bax. 6,13,14 Through the action of these E1b-encoded proteins, premature cell death is prevented and viral replication is maximized.…”