E1A signaling to p53 involves the p19^ARFtumor suppressor

Abstract

The adenovirus E1A oncogene activates p53 through a signaling pathway involving the retinoblastoma protein and the tumor suppressor p19 ARF . The ability of E1A to induce p53 and its transcriptional targets is severely compromised in ARF-null cells, which remain resistant to apoptosis following serum depletion or adriamycin treatment. Reintroduction of p19 ARF restores p53 accumulation and resensitizes ARF-null cells to apoptotic signals. Therefore, p19ARF functions as part of a p53-dependent failsafe mechanism to counter uncontrolled proliferation. Synergistic effects between the p19 ARF and DNA damage pathways in inducing p53 may contribute to E1A's ability to enhance radio-and chemosensitivity.

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins

“…Another consequence of E2F activation is the transcription of the MDM2 inhibitor p14/p19 ARF , leading to p53 accumulation and to the consequent induction of cell apoptosis (De Stanchina et al, 1998;Berk, 2005).…”

MIF loss impairs Myc-induced lymphomagenesis

“…Recent studies demonstrated that the ARF tumor suppressor inhibits cell cycle through p53-dependent and p53-independent mechanisms. [38][39][40][41][42][43] Moreover, ARF/p53 double-null B cells are more resistant to Myc-induced apoptosis than cells lacking ARF or p53 alone. 31 At face value, these results imply that the p53-independent ARF function might be selected against in MIF-KO Em-Myc B-lymphomas.…”

“…One explanation for this is that while ARF is not induced by DNA damage, it still can potentiate p53-dependent DNA damage responses that occur in the setting of Myc-induced genomic instability. 32,41,42 Frequencies of p53 and ARF mutations in MIF-KO Em-Myc mice are summarized in Table 1. Considering that only 67% of MIF-KO Em-Myc mice developed tumors by the age of 6 months (Figure 1a (Figure 4a, b).…”

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

“…As p53 plays an important role in the surveillance of oncogenic activity via p14 ARF -dependent and independent pathways (de Stanchina et al, 1998;Zindy et al, 1998), we examined whether p53 is involved in Bcl-2-mediated inhibition of MCF7 cell proliferation. Western blot analysis revealed that the p53 protein was more abundant in Bcl-2-positive cells of clones 27, 24 and 30 than in the Bcl-2-negative cells of clones 2 and 26 ( Figure 3a).…”

“…Expression of oncogenic Ras, c-Myc, E1A, E2F1, v-Abl and/or bcatenin in normal cells activates p53, at least in part, via the p14/p19 ARF tumor suppressor (Serrano et al, 1997; de Stanchina et al, 1998;Palmero et al, 1998;Zindy et al, 1998;Cong et al, 1999;Dimri et al, 2000;Damalas et al, 2001). In contrast, in colorectal cancer, expression of b-catenin induces p53 stabilization independently of p14/p19 ARF (Damalas et al, 1999).…”