Human inhibitor of apoptosis protein (IAP)survivinparticipates in regulation of chromosome segregation and mitotic exit

Abstract

A signaling cascade termed the "spindle checkpoint" monitors interactions between the kinetochores of chromosomes and spindle microtubules to prevent precocious separation of sister chromatids. We have investigated the role of human inhibitor of apoptosis protein (IAP) surviving in regulation of cell division. We demonstrate that HeLa and PtK1 cells transfected or microinjected with surviving anti-sense oligonucleotides produce significantly more polyploid and micronucleated progeny cells and show abortive mitosis when treated with spindle poisons. Furthermore, perturbation of surviving function in HeLa and PtK1 cells with anti-surviving antibodies at the beginning of mitosis affects the normal timing of separation of sister chromatids and disturbs the 3F3/2 phosphoepitope-recognized tension sensing mechanism of the spindle checkpoint. This leads to premature separation of sister chromatids, which results in an uneven distribution of chromosomes between the newly formed progeny cells-an event associated with tumor formation in many cell types. Finally, cells injected with anti-surviving antibody exit mitotic block induced with microtubule drugs. Our data suggest that surviving protein may function within the spindle checkpoint pathway.

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

“…Although survivin has been identified as an apoptosis inhibitor, it also plays a role in cell division. [55][56][57] One study demonstrated that the deletion of the survivin gene resulted in the absence of mitotic spindle, suggesting that survivin regulates chromosome segregation and cytokinesis. 58 In another study, an anti-survivin antibody application caused the premature separation of sister chromatids and the dysregulation of spindle-checkpoint activation.…”

Knockdown of survivin expression by small interfering RNA reduces the clonogenic survival of human sarcoma cell lines independently of p53

“…Furthermore, clonogenic survival of cells from each line was reduced by 65-86% (Fig 1c, Table 1). By using antisense oligonucleotides, 8,[10][11][12][34][35][36] ribozymes, 9,13,37 and siRNA (in a colon cancer cell line) 23 to knock down expression of survivin mRNA and protein, other investigators have observed a remarkable reduction in survivin mRNA that ranged from 70 to 90% and a reduction in survivin protein that ranged from 60 to 90%. The study conducted by Williams et al 23 has described the application of survivin-specific siRNA, which differs from the construct applied in our study, resulting in a reduction of survivin protein in colon cancer.…”

“…8,10,12,23,25,26 However, the fate of these polyploid cells is not completely known. Chen and co-workers suggested that many of the polyploid cells undergo apoptosis; however, we and others 12,13 did not observe a large number of these cells undergoing apoptosis. Interestingly, in the clonogenic survival assay, polyploid cells were alive after 10-14 days.…”

“…Treatment with either survivin-specific antisense oligonucleotides or ribozymes has resulted in reduced survivin expression, which has been correlated with a decrease in tumor growth in mice, with an increase in caspasedependent cell death (apoptosis), and with the formation of polyploid cells in vitro. [8][9][10][11][12][13][14][15][16] In addition to the use of antisense oligonucleotides and ribozymes, the application of small interfering RNA (siRNA) is an effective way to silence gene transcription. 17,18 Transcription silencing is thought to be a defense strategy that preserves genomes through evolution from attack by double-stranded RNA viruses and transposons.…”

The effects of knockdown of wild-type survivin, survivin-2B or survivin-Δ3 on the radiosensitization in a soft tissue sarcoma cells in vitro under different oxygen conditions

“…15 This finding is in accordance with results of survivin knockdown experiments in other cancer cell lines. 5,[16][17][18][19][20] Furthermore, survivin overexpression was associated with radioresistance in tumor cell lines. [21][22][23][24][25][26] The knockdown of survivin by ribozymes resulted in an increase of sensitivity of mt-p53 melanoma cells to irradiation.…”