Functions of Survivin

Survivin has two main functions: one as a chromosomal passenger protein and the other as an inhibitor of apoptosis. Survivin-2B has been shown to be a pro-apoptotic protein that sensitizes resistant leukemia cells to chemotherapy in a p53-dependent fashion. Survivin-Ex-3 functions as an anti-apoptotic protein and is upregulated in malignancies (Mahotka et al. 2002; Sah et al. 2006). Survivin is critical for global normal embryonic development as demonstrated by the early embryonic lethality of mice with homozygous deletions in the survivin gene locus (Wu et al. 2009). Survivin proteins are virtually absent from most normal differentiated tissues; however, these proteins are expressed in certain highly proliferative areas within normal tissues. In contrast, survivin is highly expressed in the majority of human malignancies, derived from different cell origins.

Role of Survivin in Cell Division

Survivin plays important role in the regulation of mitosis (Altieri 2003a). Survivin gene expressed in cell cycle dependent manner, and is only expressed in the G2-M phase. It is known that survivin localizes to the mitotic spindle by interaction with tubulin during mitosis, indicating its involvement in the regulation of mitosis. It is now very well documented that survivin controls multiple facets of cell division in association with other proteins. The essential role of survivin at cell division has been linked to centrosomal function (Li et al. 1998), metaphase and anaphase microtubule assembly (Giodini et al. 2002), and spindle checkpoint regulation. Depletion of survivin caused defects in cell division, such as arrest of DNA synthesis due to activation of the tumor suppressor protein p53 (Altieri 2003a, b). During anaphase of mitosis in survivin-deficient cells, sister chromatids disjoined normally, but one or more of the sister chromatids frequently lagged behind the main mass of segregating chromosomes, probably because of merotelic kinetochore attachments. Survivin-deficient cells initiated but failed to complete cytokinesis, apparently because the spindle midzone and midbody microtubules were absent during late mitosis (Caldas et al. 2005; Vivek et al. 2011). The abnormalities of both chromosome segregation and cytokinesis could be attributed to a defect in the chromosomal passenger protein complex, with a consequent mislocalization of the kinesin-like motor protein MKLP-1 associated with the microtubule abnormalities.

The RNA interference studies on the depletion of aurora B recapitulated the importance of survivin in the proliferation of normal human cells by virtue of its contributions to accurate sister chromatid segregation and assembly/stabilization of microtubules in late mitosis (Altieri 2003a). It has been demonstrated that survivin interacts with Aurora B and inner centromere protein (INCENP). This complex of AuroraB/INCENP/Survivin binds centromere of metaphase chromosomes at the central spindle midzone at the anaphase chromosome, which is characteristic of chromosomal passenger proteins that participate in chromosomal segregation and cytokinesis. Targeting survivin results in aberrant mitotic progression, leading to failed cytokinesis and multinucleation (Uren et al. 2000; Skoufias et al. 2000). Similar results reported in other organisms. A homolog of survivin, Bir1P/Cut17P/Pbh1p in fission yeast interacts with the chromosomal passenger protein (INCENP), Pic1P and the replication initiation factor Psf2P in the course of regulation of chromosomal segregation (Huang et al. 2005).

 
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