Apoptosis and Cancer


During hormone-directed expression of genetic pathways for development and differentiation of both vertebrates and invertebrates, newly forming tissues and limbs are sculpted by a proper balance of proliferation of wanted cells and apoptosis of unwanted cells. Faithful replication and propagation of genetic material by cells to their progeny through cell division, as well as the delicate balance between cell proliferation and apoptotic cell death are two important factors in maintenance of cell and tissue homeostasis. Inhibitors of apoptosis (IAP) proteins were first discovered in baculoviruses and then identified in both vertebrate and invertebrate cellular systems These proteins are typically characterized by 2-3 baculovirus IAP repeats (BIR) and a RING finger motif.

Recently, the cancer field has become greatly excited by the discovery of a single BIR-containing protein, Survivin, that functions in vertebrates to regulate both cell proliferation and apoptosis, and which is overexpressed in a majority of human cancers. However, genetic analysis of Survivin function in humans is not feasible. Therefore, our independent discovery of Deterin, the apparent Drosophila homolog of Survivin, has opened the door for the application of the power of the genetics of Drosophila in the investigation of a protein that appears involved in so many human cancers. In addition, the lack of anti-apoptosis activity of the Survivin homolog in the primitive invertebrate nematode C. elegans had raised a controversy in the field as to whether the Survivin-type proteins had anti-apoptosis activity only in the vertebrates. Our studies demonstrated that Deterin does have antiapoptotic activity against caspase-induced cell death (e.g., histogram at right). A Deterin-Survivin chimera exhibits similar activity in insect cells, demonstrating the conservation of Deterin/Survivin antiapoptotic mechanisms and validating the use of the Drosophila Deterin system as a model for Survivin-involved antiapoptotic pathways in humans.

With respect to cell-cycle or cytokinetic roles of Survivin, there has been a controversy as to the actual subcellular localization of Survivin to microtubules vs. chromosomes at various stages of the cell cycle. Our immunocytological studies on several cancer cell lines found the presence of Survivin primarily associated with centrosomes during interphase, then to chromosomes during prophase and metaphase, shifting to the midzone during anaphase and finally the midbody during telophase (see panels at right). We demonstrated that under our conditions, Survivin is not typically associated with the microtubules, but that the cancer drug taxol induces a change in localization of Survivin to the microtubules (rightmost panel).

Human caspase-7 was transfected into insect Kc cells, inducing apoptosis (blue). Cotransfection with plasmid expressing Deterin rescued cells from this apoptosis (yellow) as did a chimera of the BIR-domain of Deterin fused to the C-terminal domain of Survivin 

Jiang, X., Wilford, C., Duensing, S., Munger, K.,  Jones, G., Jones, D. Participation of Survivin in mitotic and apoptotic activities of normal and tumor-derived cells. J. Cells Biochem. 83, 342 - 54

Jones, G., Jones, D., Zhou. L.,  Stellar, H., and Chu, Y. X. (2000) Deterin, a New Inhibitor of Apoptosis from Drosophila melanogaster. J. Biol. Chem. 29, 22157 - 22165

Xu Y, Fang F, Ludewig G, Jones G, Jones D. (2004).  A mutation found in the promoter region of the human survivin gene is correlated to overexpression of survivin in cancer cells.DNA Cell Biol. 23(7):419-29.