Survivin and IAP proteins in cell-death mechanisms

Abstract

From the realization that cell number homoeostasis is fundamental to the biology of all metazoans, and that deregulation of this process leads to human diseases, enormous interest has been devoted over the last two decades to map the requirements of cell death and cell survival. This effort has led to tangible progress, and we can now chart with reasonable accuracy complex signalling circuitries controlling cell-fate decisions. Some of this knowledge has translated into novel therapeutics, and the outcome of these strategies, especially in cancer, is eagerly awaited. However, the function of cell-death modifiers have considerably broadened over the last few years, and these molecules are increasingly recognized as arbiters of cellular homoeostasis, from cell division, to intracellular signalling to cellular adaptation. This panoply of functions is best exemplified by members of the IAP (inhibitor of apoptosis) gene family, molecules originally narrowly defined as endogenous caspase inhibitors, but now firmly positioned at the crossroads of multiple normal and transformed cellular responses.

Figure 1. Schematic diagram of domain structure in representative IAP proteins

The individual domains found in IAPs and how they are variously assembled in representative members of the IAP gene family are shown. BIR, Baculovirus IAP repeat; CARD, caspaserecruitment domain; DIAP1, Drosophila IAP1, UBA, binding site for poly-ubiquitinated proteins.

Figure 2. Survivin cytoprotection involves a pathway of cytoplasmic-mitochondrial shuttling and intermolecular cooperation with XIAP

A pool of survivin is recruited to mitochondria, mostly of tumor cells and released in the cytosol in response to cell death stimuli. Mitochondrially released survivin forms a complex with XIAP that is negatively regulated by protein kinase A (PKA) phosphorylation of survivin on Ser20, and results in increased XIAP stability against proteasomal degradation, enhanced gene expression, i.e. NF-κB, and synergistic inhibition of effector and initiator caspases (a schematic diagram of caspase 9 is shown).

Figure 3. Role of survivin in the cellular stress response

The various functional motifs in survivin are indicated, including the binding sites for protein partners, XIAP (residues 15-38), Hsp90 (residues 79-87), polymerized microtubules (residues 99-142), and AIP (residue 142), and the position of experimentally validated phosphorylation sites for PKA (Ser20) p34^cdc2/Cdk1 (Thr34) and Aurora B (Thr117). The survivin binding site for Hsp60 has not yet been identified. Formation of complexes between survivin and molecular chaperones Hsp60, Hsp90 and AIP has been associated with increased survivin stability against proteasomal degradation, nuclear and mitochondrial subcellular trafficking, and inhibition of apoptosis.