Figure 1.

Proposed model for the mechanisms culminating in cell death and immune activation upon p19Arf and interferon-β gene transfer. Initially, on remediation of p19Arf by the AdRGD-PGp19Arf adenoviral vector, p53 becomes free-form MDM2 and activates its pro-apoptotic pathway, evidenced by upregulation of its target genes, caspase-3 activity and Bax protein levels. Just as Arf is not strong enough to cause massive cell death on its own, IFNβ by itself mainly inhibits proliferation and potentiates an antiviral and immunostimulatory response, facilitated by the presence of adenovirus components. Combined activation of these pathways provides a stimulus strong enough for the efficient killing of melanoma cells. This process of cell death displays features of necroptosis, suggested by RIP3 expression, upregulation of the TNF receptor, absence of caspase-3 activity and most importantly, immunogenic cell death markers (ATP, calreticulin, HMGB1), along with IFNβ, to promote an antitumor immune response mediated by NK cells, CD4+ and CD8+ T lymphocytes