This 208-residue skeletal and cardiac muscle protein (MW = 22629.46 g; Protein Accession Number AAC34993; Isoelectric Point = 4.11), known fully as Apoptosis Repressor with CARD (or Caspase recruitment domain), is an endogenous inhibitor of apoptosis that is induced by caspase-8 and CED-3, but not caspase-9. Significantly, the enzymatic activity of caspase- 8 is inhibited by ARC in 293T cells. Consistent with the inhibition of caspase-8, ARC attenuates apoptosis induced by FADD and TRADD as well as that triggered by stimulation of caspase-8 death receptors (e.g., CD95/Fas, tumor necrosis factor-R1, and TRAMP/DR3). ARC also antagonizes both the extrinsic (death receptor) and intrinsic(mitochondrial/ER) pathways. ARC also inhibits TNFα-induced necrosis when overexpressed in its wild-type form, but not by a CARD mutant defective for inhibiting apoptosis. Conversely, knockdown of ARC exacerbated TNFα-induced necrosis, an effect that was rescued by reconstitution with wild type ARC, but not with CARD-defective ARC. A likely mechanism for these effects involves the interaction of ARC with TNF Receptor-1, interfering with recruitment of RIP1, a critical mediator of TNFα-induced regulated necrosis. Induction of hypoxia-inducible factors (HIFs) is needed for tumor cell to adapt to a low-oxygen environment, and ARC expression is itself induced in a HIF1-dependent manner.
