Molecular mechanisms for radiosensitive apoptosis in mouse pre-T cells

Abstract

We investigated the molecular mechanisms by which mouse pre-T ST4 and STH1a cells (gift of I. Radford) undergo the hyper-radiosensitive apoptosis. One pathway was the p53-driven upregulation of BH3-only Puma, Bim and Noxa, which activated Bax and Bak to release cytochrome c from mitochondria and activate the caspase-9—capsase-3/7 cascade. Another pathway relied on the caspase-2 activation via p53-mediated PPIDosome. Independent of the above pathway, caspase-2 was inactivated by VDVAD-CHO or caspase-2 siRNA. Rrather than IR-irresponsive caspase-8 in these cells, furthermore, active caspase-2 had a novel role for Bid cleavage to tBid, which plays a role in Cytc release for DNA damage-induced, p53-dependent apoptosis. Thus, the above two pathways are the molecular basis of hyper-radiosensitive apoptosis in ST4 and STH1a cells.