Survivin

Survivin is a member of the inhibitor of apoptosis (IAP) gene family, which is positioned at the interface between mitotic progression and apoptosis inibition (27).

The human survivin gene spans 14.7 kb on the telomeric position of chromosome 17 and is localized to band q25 (28). It comprises three introns and four exons, a TATA-less proximal promoter, and approx 200-nt GC-rich regions upstream of exon 1 (29). The gene encodes a 16.5-kD protein of 142 amino acids. Structurally, it is composed of a single baculovirus IAP repeat domain and an extended COOH-terminal a-helical coiled-coil domain (30). Moreover, it does not contain a RING-finger domain, found in other IAPs. Splicing variants of survivin have been identified. Survivin-2B is generated by insertion of an alternative exon, survivin-AEx3 arises from the removal of the exon 3, and survivin-3B results from the introduction of a novel exon 3B (31,32). Very recently, an additional splice variant, survivin 2a, has been identified. Structurally, the transcript consists of two exons: exon 1 and exon 2, as well as a 3' 197-bp region of intron 2. Acquisition of a new in-frame stop codon within intron 2 results in an open reading frame of 225 nt, predicting a truncated 74-amino acid protein (33). Little is known about the differential functions of survivin alternative splice forms. However, preliminary data would suggest that heterodimer-ization of survivin with survivin-AEx3 is essential for the inhibition of mitochondrial-dependent apoptosis (34). Moreover, it has been demonstrated in exogenous expression assays that survivin 2a attenuates the antiapoptotic activity of survivin (33).

Survivin is regulated in a highly cell cycle-dependent manner, with a marked increase in the G2/M phase (35). During this phase, survivin associates with and is phosphorylated by p34cdc2/cyclin B1 kinase (36). It has been demonstrated that survivin exists in two immunohistochemically distinct pools, with a nuclear pool localized to kinetochores of metaphase chromosomes and to the central spindle midzone at anaphase, and a cytosolic pool associated with interphase microtubules, centrosomes, spindle poles, and mitotic spindle microtubules at metaphase and anaphase (37). However, the microtubule-associated pool appears to be quantitatively predominant and functionally relevant. These findings, together with the phenotype of knockout mice (which is characterized by a catastrophic defect of microtubule assembly, with absence of mitotic spindle, formation of multinucleated cells and 100% embryonic lethality 138]), are consistent with a critical role of survivin in mitosis to preserve the mitotic apparatus and to allow normal mitotic progression. In fact, it has been demonstrated that survivin downregulation causes pleiotropic cell-division defects (39,40). Moreover, Giodini et al. (41) showed that forced expression of survivin in HeLa epithelial carcinoma cells profoundly influenced microtubule dynamics and also caused stabilization of microtubules against nocodazole-induced depolymeriza-tion, thus indicating that survivin may facilitate evasion from checkpoint mechanisms of growth arrest and, consequently, promote resistance to drugs targeting the mitotic spindle. Additional evidence indicates that survivin also participates in the regulation of chromosome segregation (42), and that the protein cooperates together with the chromosomal passenger proteins INCENP and Aurora-B to perform its mitotic duties (43). The existence of a mitochondrial pool of sur-vivin, which is able to orchestrate a novel pathway of apoptosis inhibition in tumor cells, has been recently reported (44). Specifically, it was found that, in response to cell death stimulation, mitochondrial survivin is rapidly discharged in the cytosol, where it prevents caspase activation and inhibits apoptosis.

It has been demonstrated that Hsp90, a molecular chaperone that is the central regulator of cellular stress response, associates with survivin. Such a physical interaction, which involves the Hsp90 ATPase domain and the survivin baculovirus IAP repeat domain, is required for survivin stability and function. In fact, targeted antibody-mediated disruption of the survivin-Hsp90 complex in cancer cells resulted in proteasomal degradation of survivin (45).

In regard to the precise role of survivin in cell death, at present it is still controversial whether this protein inhibits caspases through direct binding, as other IAPs do, or indirectly, requiring intermediate proteins. In this context, a possible direct interaction of survivin with caspase-9 has been reported by O'Connor et al. (46) whereas more recently Song et al. (47) suggested an alternative model for indirect inhibition of caspases by survivin, which requires Smac/Diablo as intermediate protein. This mitochondrial factor, that is released into the cytosol in response to different apoptotic stimuli, was found to bind to some IAPs (including XIAP, cIAPp cIAP2, and livin), thus preventing them from inhibiting caspases (48). The ability of survivin to physically interact with Smac/Diablo and, as a consequence, sequester it would allow other IAPs to block caspases without being antagonized.

Survivin is strongly expressed in embryonic and fetal organs but not in differentiated normal tissues with the exception of thymus, basal colonic epithelium (49) endothelial cells, and neural stem cells during angiogenesis (50). Several reports have demonstrated survivin expression in the majority of human tumor types including lung, breast, colon, gastric, oesophageal, pancreatic, liver, bladder, uterine, and ovarian cancers, large-cell non-Hodgkin's lymphomas, leukemias, neuroblastoma, brain tumors, pheochromocytoma, soft-tissue sarcomas, melanomas, and other skin cancers (49). Moreover, the expression of survivin has been also detected in a variety of preneoplastic and/or benign lesions including polyps of the colon, breast adenomas, Bowen's disease, and hypertrophic actinic keratosis (49), suggesting that reexpression of survivin may occur early during malignant transformation or following disturbance in the balance between cell proliferation and death. The upregulation of survivin at the transcriptional level in human tumors has been confirmed in genome-wide searches, which indicated survivin as the fourth top "transcriptome" in cancers of various histology (51). At least for some tumor types, molecular abnormalities have been described that may account for the increased expression of survivin in cancer compared to normal tissue. Specifically, in neuroblastoma a gain of 17q25 containing the survivin locus represents a frequent genetic abnormality (52). Moreover, in most ovarian cancers survivin exon 1, which is silenced by methylation in normal ovarian epithelium, becomes unmethylated and, consequently, transcriptionally active (53). Survivin overexpression in tumors has been recently linked to the loss of wild-type p53 (54). Specifically, it was seen that accumulation of wild-type p53 in human ovarian cancer cells induced survivin transcriptional repression, which did not require direct sequence-specific DNA binding of p53 to the survivin promoter. Modifications of chromatin structure within the promoter could be the molecular explanation for silencing of the survivin gene by wild-type p53.

In the majority of tumors investigated for survivin expression (including breast, lung, colorectal, gastric, liver, bladder, and kidney cancers, neuroblastoma, gliomas, soft tissue sarcomas, leukemias, and lymphomas), high levels of the protein were predictive of tumor progression, either in terms of disease-free survival or overall survival, thus providing prognostically relevant informations (49). In several neoplasms, the association with tumor progression has been also corroborated in the context of comprehensive analysis of gene-expression profiling by DNA microarray or PCR-based assays.

Considering that apoptosis is the primary mode of cell death induced by several classes of anticancer agents and ionizing radiation, a possible general role of sur-vivin in determining the chemo- and radio-sensitivity profiles of tumor cells has been hypothesised. Moreover, because survivin is associated with microtubules and with the mitotic spindle it is likely that this protein can specifically contribute to the response of cells to microtubule-interacting agents. Li et al. (55) first demonstrated that transfection of wild-type survivin efficiently protected murine NIH3T3 fibroblasts from apoptosis induced by the microtubule-stabilizing agent taxol. In agreement with this observation, Giodini et al. (41) reported that infection of HeLa cells with an adenoviral vector expressing survivin suppressed apoptosis induced by taxol. Based on this finding, our laboratory performed a parallel investigation on cell lines and clinical specimens from ovarian carcinomas to determine whether survivin is involved in regulating cell sensitivity to taxanes. The OAW42 and IGROV-1 human ovarian cancer cell lines were transfected with the human survivin cDNA. Stable transfection with survivin cDNA was able to protect these cells from the cytotoxic effects induced by taxol and taxotere (56). In the clinical setting, when we analyzed the response of advanced ovarian cancer patients to a taxol/platinum-based regimen as a function of survivin expression, we found a significantly higher clinical or pathologic response rate in cases with absent/low protein expression than in those expressing high levels of survivin (56).

Regarding the possible role of survivin in determining the radiation response of human tumor cells, Asanuma et al. (57) reported that survivin acts as a constitutive radio-resistance factor in pancreatic cancer cells. Specifically, in a panel of established cell lines they found an inverse relationship between survivin mRNA expression and in vitro sensitivity to X-irradiation. Moreover, these authors also demonstrated that survivin mRNA expression was increased by sublethal doses of X-irradiation, which would suggest that the protein also acts as an inducible radio-resistance factor.

Very recently, Zhang et al. (58) showed that survivin mediates resistance to antiandrogen therapy with flutamide in prostate cancer cells. Specifically, these authors suggested that upregulation of survivin via insulin-like growth factor-1/AKT signaling during androgen blockade may be one of the mechanisms by which prostate cancer cells develop resistance to antiandrogens.

Overall, the results obtained in the different studies indicate survivin to be a cellular factor potentially involved in the chemo- and radio-resistant pheno-types of human tumors cells and suggest that approaches designed to inhibit survivin expression may lead to human tumor sensitization to chemical and physical agents. In recent years, considerable efforts have been made by researchers to develop strategies for modulating apoptosis in cancer and other human diseases (59,60). In this context, approaches to counteract survivin in tumor cells have been proposed with the dual aim to inhibit tumor growth through an increase of spontaneous apoptosis, and to enhance tumor cell response to apoptosis-inducing agents (61). Different kinds of survivin molecular inhibitors, including antisense oligonucleotides, dominant negative mutants, and cyclin-dependent kinase inhibitors have been used.

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