Pro-survival activities of the cancer-associated protein survivin

Survivin is a small adaptor protein that is upregulated in all human cancers and whose expression dictates a poor prognosis for the patients, and likely resistance to chemo- and radiation therapies. While the expression of survivin in cancer cells clearly confers a survival advantage, the mechanism(s) by which it achieves this are still largely unknown. At the molecular level survivin acts in consort with several mitotic proteins including aurora-B kinase, borealin and INCENP to ensure that chromosomes are correctly attached to the mitotic spindle before the cell segregates them into the daughter cells. These proteins, which are collectively referred to as the chromosomal passenger complex (CPC), also regulate cytokinesis and are essential for cell proliferation and this aspect of survivin biology is the best understood.

In addition to its role as part of the CPC, survivin can also inhibit cell death and is a member of the inhibitor or apoptosis family of proteins (IAPs), which bind to and inhibit the activity of the death effector proteins, the caspases. However, unlike its IAP family members, survivin lacks the specific caspase interaction sites thought to be required for direct interaction with caspases. Thus while it is uncontested that survivin overexpression reduces caspase activity, how it achieves this remains unclear. Further pro-survival roles of survivin have recently begun to emerge, and of particular interest to our lab is its role in mitochondrial health, metabolism and autophagy.

The aim of this project is to dissect that molecular pathways that permit this fascinating little protein to prevent cancer cells from programmed cell death.

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