Table of Contents

Israeli Principal Investigator

Atan Gross
Weizmann Institute of Science, Department of Biological Regulation, Rehovot, Israel

DKFZ Principal Investigator

Henning Walczak
Division of Apoptosis Regulation (D040)

Approaches and Achievements

Endogenous BID is predominantly expressed in the nucleus in mouse embryonic fibroblasts. The picture was generated using the immunofluorescence technique with anti-BID antibodies that specifically mark cellular BID with a green colour. | © dkfz.de

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent as it selectively kills tumour cells but spares normal cells from cell death. However, resistance to TRAIL by many tumour cells limits its therapeutic use. The initial signal emanating from TRAIL-R1 and/or TRAIL-R2 is not always capable of directly inducing apoptosis. In dependency of XIAP expression some cell types, so called type II cells, require caspase-8/10-mediated cleavage of the BH3-only protein Bid for apoptosis induction by TRAIL. The C-terminal fragment of Bid, referred to as truncated Bid (tBid), translocates to mitochondria and triggers the mitochondrial apoptotic response resulting in release of apoptogenic factors, thereby inducing cell death. Several post-translational modifications have been described to influence the pro-apoptotic function of Bid, amongst them a phosphorylation of Bid at serine residue 78 (S78) upon DNA damage by the ataxia telangiectasia mutated (ATM) kinase. This phosphorylation renders Bid to function as a pro-survival molecule in mice, a role which has recently been contested. We aimed to investigate a potential role of the DNA damage-mediated phosphorylation of Bid at S78 in TRAIL-induced apoptosis. We could demonstrate that this phosphorylation of Bid also occurs in human cancer cells in an ATM-dependent manner, pointing towards a conserved mechanism of Bid phosphorylation. However surprisingly, treatment of tumour cell lines with TRAIL alone already results in phosphorylation of tBid at residue S78. Intriguingly, in contrast to DNA damage-induced phosphorylation of Bid, TRAIL-induced phosphorylation of tBid on S78 turned out not to be mediated by ATM as ATM knockdown cells still showed TRAIL-induced phosphorylation of tBid. The functional role of TRAIL-induced phosphorylation of tBid remains to be determined.