The human survivin gene was first cloned and described by Ambrosini et al. in 1997 as a unique and smallest member of inhibitor of apoptosis protein family (IAP) (Ambrosini et al. 1997). IAPs are diverse group of signaling molecules with wide range of physiological role, from the inhibition of apoptosis to cell cycle progression. IAPs have nine family members: X-linked IAP, cIAP1, cIAP2, neuronal apoptosis inhibitor protein, melanoma IAP, IAP-like protein 2, livin, apollon, and survivin. The first IAP was isolated as a baculovirus gene product and identified by the presence of baculovirus IAP repeat (BIR). All the members of IAP family are generally characterized by presence of one or more copies of BIR at N-terminus and ring finger domain at their carboxyl terminus except survivin which contains a single BIR domain but no ring finger motif as it is replaced by an alpha helix coil. The BIR domain is supposed to be important for antiapoptotic function, whereas the coiled domain probably interacts with tubulin structures in mammals (Jaiswal et al. 2015).
Structure and Transcription
Expression and Regulation of Its Transcription
Survivin in Normal Cells
Survivin is strongly expressed in fetal tissue, whereas its expression in normal adult tissue is developmentally regulated and reported to be minimal in most terminally differentiated tissues. Its physiologic expression in normal cells/tissues is limited to T cells (peripheral blood adult T cell, thymocytes, memory T cells), CD34+ cells (cord blood, adult bone marrow cells), neutrophils, megakaryocytes, arterial muscle, gastrointestinal tract mucosa, keratinocyte, melanocyte, brain, cervical mucosa, ovary, testis, breast, and placenta (Fukuda and Pelus 2006).
Distribution of survivin and its splicing variant in subcellular compartments is also elucidated. Wild-type survivin and survivin-2B predominantly localize in cytoplasm. Whereas, survivin-2α, almost equally between the cytoplasm and nucleus, but survivin-ΔEx3 localizes in both the mitochondria and nucleus. However, in mitotic cells, survivin-ΔEx3 appeared to translocate and colocalize with the mitotic spindle (Li et al. 2005).
In Vascular Endothelial Cells
Expression of survivin in normal endothelial cells is regulated by the angiogenic cytokines, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin 1, and hypoxia/reoxygenation through a cascade of phosphatidylinositol 3-kinase/Akt pathway. Experimental studies in human umbilical vascular endothelial cells (HUVEC) suggested the role of angiopoietin 1 and interleukin-11 in survivin-mediated inhibition of apoptosis via forkhead-related transcription factor pathway and signal transducer and activator of transcription-3 pathway, respectively.
In Hematopoiesis and Blood Cells
Differential expression of survivin is noticed during erythroid versus megakaryocyte development as survivin is noticed to be expressed in maturing erythroid cells, whereas it’s no to little expression in murine megakaryocytes like myeloid progenitor cells suggesting that survivin expression is required in megakaryocytes and erythroid progenitor cells and that survivin plays a significant role in erythropoiesis. Interestingly, survivin downregulation is an essential component of megakaryocyte maturation and thus may play a role in platelet formation. Consistent high level of survivin expression in CD34+ hematopoietic stem and progenitor cells, as compared with lineage-committed CD34− cells or blood mononuclear cells, indicates its downregulation with maturation of differentiation of hematopoietic cells.
Likewise, expression of survivin diminishes in mature blood neutrophils as compared with its immature counterpart. But in vitro and in vivo upregulation of survivin in mature neutrophils could be achieved through stimulation with neutrophil growth and survival factors (granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor) and inflammatory conditions, respectively.
Expression of survivin in splenic T cells and human adult peripheral blood T lymphocytes can be induced by interleukin-2 plus anti-CD3, concanavalin A (7), or phytohemagglutinin. But for effector T cell proliferation, induction of survivin by co-stimulatory signal of OX40 is required during late G1 phase.
In Adult Stem Cells
The putative role of survivin in embryological development and maintenance of adult stem cells is supported by cumulative evidences of its expression in these CD34+ totipotent cells. Hematopoietic growth factors, i.e., thrombopoietin, stem cell factor, and Flt3 ligand, stimulate proliferation, cell cycle progression, and survival of CD34+ cells by upregulation of survivin expression through downstream of mitogen-activated protein kinase p42/p44 and phosphatidylinositol 3-kinase. In addition, survivin-mediated inhibition of apoptosis of hematopoietic progenitor cells via a p21-dependent mechanism suggests a functional link between survivin and p21 in regulating hematopoietic cell division.
In Other Adult Tissues
Survivin in Tumor Cells
Survivin is predominantly present in the cytosol of tumor cells with minimal nuclear expression mainly restricted to kinetochores of metaphase chromosomes. Cytosolic survivin is believed to function as apoptotic suppressor, while nuclear survivin is postulated to regulate cell division. Mitochondrial survivin has been also detected and also shown to be released to cytosol in response to cellular stress and stimuli. Additionally, extracellular pool of survivin has also been shown to exist as exosomes (40–100 nm membrane vesicles) secreted from tumor cells and taken up by surrounding cells. The exosomal survivin is believed to have the ability to empower the tumor cells by proliferation and invasive potential and resistance to the therapy and finally act as a negative predictor of prognosis (Garg et al. 2016).
Survivin and Embryonic Development
Till now, various experimental studies suggested that survivin shows a strict regulated expression during embryonic development and play an important biphasic role in the control of embryonic cell mitosis/cytokinesis and apoptosis. During mitosis, function of survivin mainly focuses at metaphase and anaphase and localizes to two main subcellular pools. One pool of survivin is directly associated with centrosomes, microtubules of the metaphase and anaphase spindle, suggesting its regulatory role in microtubule dynamics. The second pool of survivin restricted to the kinetochores of metaphase chromosomes which is associated with regulators of cytokinesis, i.e., subunits of the chromosomal passenger complex (CPC), such as Aurora B kinase, INCENP, and Borealin/Dasra. This supports a vital role of survivin in proper chromosome segregation and cytokinesis. Recently another putative role of survivin as a central regulator of spindle formation is proposed, which explains its contribution in proper targeting of CPC to kinetochores and, in addition, stabilization of the microtubules, thus contributing to bipolar spindle formation. In mouse embryos, survivin showed a strong expression in several apoptosis-regulated fetal tissues with a pattern independent of Bcl-2, suggesting its pivotal role in organogenesis (Chen et al. 2016; Li 2003). Even in mouse preimplantation embryos, expression of survivin and its splice variants are observed in several stages of embryogenesis from unfertilized oocyte to blastocyst stage. Disrupted microtubules leading to formation of polypoid and survival failure in Null embryos furthermore support the unique role of survivin in mitosis. On the other hand, few experimental studies which also revealed the survivin knockout in early mouse embryo show induction of apoptosis in addition to disrupted mitosis mainly in neuronal cells of the central nervous system (Altieri 2003; Mita et al. 2008).
Though various postulations have been laid down, the role of survivin in inhibition of apoptosis is controversial. Initially, selective binding and degradation of activated caspases, i.e., 3 ,7, 9 by survivin, have been suggested. This model was challenged by observations like survivin lacks structural motifs necessary for caspase binding. Later on, few researchers suggested inhibition of caspase-9 by survivin through its binding with hepatitis B X-interaction protein (HBXIP) to procaspase-9. Furthermore, antiapoptotic role of survivin could be explained by its association with X-linked IAP via their conserved BIR domain, thus increasing X-linked IAP stability and leading to the synergistic inhibition of caspase-9 activation. Finally, another mechanism of inhibition of intrinsic pathway of apoptosis by survivin gained some attention as it explains direct binding of survivin to proapoptotic protein (secondary mitochondria-derived activator of caspase, SMAC/DIABLO), an activator of caspase-9 (Chen et al. 2016; Li 2003).
Survivin in Tumor Biology
Inhibition of apoptosis has been widely reported in a number of cancers such as breast, liver, and lung cancers. Overexpression of survivin is associated with inhibition of cell death initiated via the extrinsic or intrinsic apoptotic pathways. Interestingly, contradiction on the interaction between survivin and caspases has been reported. Few studies indicate direct inhibition of caspase-3, 7, and 9 by survivin, whereas others support indirect mechanisms like inhibition cytochrome c- and caspase-8-induced DEVD (Asp-Glu-Val-Asp) cleavage activity, thus resulting in decreased activity.
The cell cycle-specific regulation of survivin has been highlighted in many experimental and clinical researches. Multiple roles of survivin are suggested such as survivin-mediated mitosis after phosphorylation by CDK1 (cyclin-dependent kinase-1) and acceleration of S-phase through survivin-CDK4 interaction mainly in hepatoma cells.
- (iii).Survivin can influence the cell survival by affecting both the apoptosis and cell cycle progression through interaction with a master molecule, i.e., p53. A variety of studies have suggested the functional association of these molecules in the view of following observations like:
Presence of two putative p53 binding sites within the survivin promoter.
Consistent and aberrant expression of survivin and disruption of wild-type p53 in association with tumorigenesis.
Antagonism in function like wild-type p53, but not mutated p53, can repress survivin transcriptional level, and that survivin loss of function partially mediates the p53-dependent apoptotic pathway.
Chromatin deacetylation of the survivin promoter suggests that modification of chromatin may contribute to survivin expression silencing by p53. In addition, survivin regulates p53 expression as it modifies p53 degradation through the caspase-3/mouse double minute two homologue (MDM2) complex, mainly in lung and breast cancer.
Increased evidences of regulation of angiogenesis in tumor cells by upregulation of vascular endothelial cell growth factor (VEGF) denote about the survivin-mediated tumor progression. Though the exact mechanism is not much explored, induction of VEGF by PI3K/Akt enhanced β-catenin-Tcf/Lef-dependent transcription has been largely suggested.
- (v).Survivin-mediated cell proliferation pathways: In multiple cancers like breast, colorectal, lung, and prostate cancers and melanoma, the role of survivin-mediated Wnt/β catenin signaling pathway has been highlighted in tumorigenesis as Wnt signaling induces nuclear translocation of β-catenin to form β-catenin/T cell factor (TCF) transcriptional activator. This complex upregulates survivin transcription. Similarly, in hypoxia, hypoxia-inducible factor-1 transcription factor can regulate the survivin expression by direct binding to its promoter. It has been also observed that Notch-1 signaling activation is associated with elevated HIF-1α, which functions as a coactivator by interacting with activated form of Notch-1 (N1ICD, Notch-1 intracellular domain), following the association of RBP-Jκ (recombination signal binding protein for immunoglobulin kappa J region) to the survivin promoter, finally leading to the transcriptional activation of survivin. Likewise, STAT3 also plays a vital role in survivin-mediated tumor cell proliferation by its influence on survivin transcription. Additionally, structural similarity between these molecules imparts effect on inhibition of STAT3 transactivation following lysine acetylation of survivin (Chen et al. 2016; Garg 2016).
Currently, there is no impactful evidence suggesting an association of survivin splicing variant with tumorigenesis. Few clinical research studies indicated the altered expression of survivin-ΔEx3, survivin-2B, and survivin in gastric cancer, irrespective of clinicopathological parameters like their histological type, grade, or stage. Interestingly, observations like the level of survivin-ΔEx3 is shown to be inversely correlated with apoptotic index and structural resemblance of survivin-ΔEx3 to novel antiapoptotic protein encoded by open reading frame K7 of Kaposi’s sarcoma-associated herpesvirus are suggestive of its putative antiapoptotic role. It is also reported that survivin-2B expression was prominent in benign rather than the malignant benign tumors, whereas survivin-ΔEx3 expression was increased in comparison with survivin-2B expression in leukemia patients. In addition, the unlikely subcellular localization of survivin-ΔEx3 (in nucleus) and survivin-2B (in cytoplasm) also suggests their potential contrast roles in tumor progression and/or tumorigenesis (Li 2005; Li et al. 2005).
Since its discovery, various in vitro and in vivo studies suggested the diverse role of survivin in physiological and pathological conditions as an antiapoptotic molecule, regulator of mitosis/cytokinesis, and angiogenesis promoter. Furthermore, mounting evidences like involvement of survivin in multiple proliferation signaling pathways and clinical correlation with tumor progression, therapeutic resistance, and poor prognosis open the opportunity for development of suitable individualized therapeutic strategies like immunotherapy Ad gene therapy targeting survivin with more efficiency and specificity for tumor cells, but minimal cytotoxicity against healthy cells.