title: Caspase-3 mediated release of SAC domain containing fragment from Par-4 is necessary for the sphingosine-induced apoptosis in Jurkat cells.
abstract: BACKGROUND
  Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that selectively activates and induces apoptosis in cancer cells, but not in normal cells. The cancer specific pro-apoptotic function of Par-4 is encoded in its centrally located SAC (Selective for Apoptosis induction in Cancer cells) domain (amino acids 137-195). The SAC domain itself is capable of nuclear entry, caspase activation, inhibition of NF-κB activity, and induction of apoptosis in cancer cells. However, the precise mechanism(s) of how the SAC domain is released from Par-4, in response to apoptotic stimulation, is not well explored.
  
  
  RESULTS
  In this study, we demonstrate for the first time that sphingosine (SPH), a member of the sphingolipid family, induces caspase-dependant cleavage of Par-4, leading to the release of SAC domain containing fragment from it. Par-4 is cleaved at the EEPD131G site on incubation with caspase-3 in vitro, and by treating cells with several anti-cancer agents. The caspase-3 mediated cleavage of Par-4 is blocked by addition of the pan-caspase inhibitor z-VAD-fmk, caspase-3 specific inhibitor Ac-DEVD-CHO, and by introduction of alanine substitution for D131 residue. Moreover, suppression of SPH-induced Akt dephosphorylation also abrogated the caspase dependant cleavage of Par-4.
  
  
  CONCLUSIONS
  Evidence provided here shows that Par-4 is cleaved by caspase-3 during SPH-induced apoptosis. Cleavage of Par-4 leads to the generation of SAC domain containing fragment which may possibly be essential and sufficient to induce or augment apoptosis in cancer cells.
authors: Cell Signaling Laboratory, Department of Biochemistry, College of Medicine and Health Sciences, UAE University, P,O, Box 17666, Al Ain, Abu Dhabi, UAE. sehamuddin@uaeu.ac.ae.
authors: Faisal
authors: F
authors: Thayyullathil
authors: Siraj
authors: S
authors: Pallichankandy
authors: Anees
authors: A
authors: Rahman
authors: Jaleel
authors: J
authors: Kizhakkayil
authors: Shahanas
authors: S
authors: Chathoth
authors: Mahendra
authors: M
authors: Patel
authors: Sehamuddin
authors: S
authors: Galadari