Figure 6. Model for the role of RPOA-2 and Ras/MAPK in determining apoptosis.A) Model for the effect of
rpoa-2(
op259) on the apoptotic network via the Ras/MAPK pathway. CEP-1/p53 activity is induced by irradiation, and increased at baseline in
rpoa-2(
op259) by an unknown mechanism, but this results in only little germ cell apoptosis.
rpoa-2(
op259) thus has an additional inhibitory effect on apoptosis downstream of CEP-1 activation, at the level of the core apoptotic machinery (possibly at the level of CED-9).
rpoa-2(
op259) leads to reduced levels of activated MPK-1 and genetic overactivation of Ras/MAPK restores IR-induced germ cell apoptosis levels in
rpoa-2(
op259) animals, suggesting that this pathway provides the link.
rpoa-2(
op259) might influence Ras/MAPK activity by affecting the phosphatase LIP-1. B) Model for the role of the Ras/MAPK pathway as a central and general modulator of germ cell apoptosis levels. Classically, DNA damage-induced and constitutive 'physiological' germ cell death have been distinguished, genetically converging only at the level of the core apoptotic machinery. We and others see that the level of Ras/MAPK pathway activity is decisive for the extent of germ cell death, both at standard growth conditions and following ionising irradiation. Furthermore, activated MPK-1 levels are increased soon after irradiation treatment. For constitutive cell death, it remains to be resolved whether Ras/MAPK pathway activity is simply permissive or whether it is a direct part of the induction signalling. Overall, MAP kinase pathways could be acting as a master lever for the sensitivity of germ cells towards further pro-apoptotic stimuli.