FIGURE 2.

ARF impinges both on developmental processes (male germ cell development and ocular development in mice) and tumor angiogenesis. ARF is essential for normal spermatogenesis in mice possibly through interacting with the meiotic repair machinery. In the ocular development of the mouse, ARF is required for the involution of the hyaloid vascular system (HVS); a transient network of vessels that provides nutrients to the developing oculus. This is accomplished via a pathway in which ARF blocks platelet-derived growth factor receptor β (PDGFRβ)-dependent signaling which in turn, is necessary for the investment of vessels by mural cells and their maintenance. This may also be possibly regulated via the ARF-dependent inhibition of internal ribosome entry site (IRES)-mediated translation of PDGFRβ. ARF can also suppress the IRES-mediated translation of vascular endothelial growth factor A (VEGFA), thereby inhibiting tumor angiogenesis. Unpublished data indicate that the stabilization of endogenous ARF upon inhibition of ataxia-telangiectasia mutated (ATM) kinase activity can also result in a decrease in VEGF levels; although it is not known whether the underlying mechanism involves the suppression of IRES-mediated translation of VEGF or an IRES-independent route. It may even involve a route that is not associated with the control of VEGF at the translational level. (The ATM/ARF/VEGF pathway is shown by lines.) ATM kinase itself, independently of ARF, has also been incriminated in pathological angiogenesis in adult mouse oculus and cancer (Kerr and Byzova, 2012), but these effects are not depicted here for reasons of clarity. (HA, hyaloid artery.)