Model for ARF signaling. ARF is
activated via Myc and E2F-1 and acts in turn to trigger p53-dependent
cell cycle arrest or apoptosis, depending on the presence of
extracellular survival factors. Ras acts through cyclin D-dependent
kinases to stimulate pRB phosphorylation, resulting in release of E2F
from pRb constraint and activation of E2F-responsive genes.
Activation of ARF by MYC and E2F-1 need not be direct,
although both transcription factors have been demonstrated to increase
ARF mRNA levels (see text). Like Myc, different E2F
isoforms are proposed to regulate both cell growth and cell death. In
inhibiting cyclin D-dependent kinases, p16INK4a can modulate
certain growth-promoting functions of Ras. Other functions of Myc and
Ras are not detailed in the schematic.