Title

Acute ablation of survivin uncovers p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis

UMMS Affiliation

Department of Cancer Biology and the Cancer Center

Publication Date

10-29-2003

Document Type

Article

Subjects

*Apoptosis; Hela Cells; Humans; Microtubule-Associated Proteins; inhibitors; Mitochondria; *Mitosis; Neoplasm Proteins; Polyploidy; RNA Interference; Tumor Suppressor Protein p53

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Survivin is a member of the Inhibitor of Apoptosis gene family that has been implicated in cell division and suppression of apoptosis. Here, we show that preferential ablation of the nuclear pool of survivin by RNA interference produces a mitotic arrest followed by re-entry into the cell cycle and polyploidy. Survivin ablation causes multiple centrosomal defects, aberrant multipolar spindle formation, and chromatin missegregation, and these phenotypes are exacerbated by loss of the cell cycle regulator, p21(Waf1/Cip1) in p21(-/-) cells. The mitotic checkpoint activated by loss of survivin is mediated by induction of p53 and associated with increased expression of its downstream target, p21(Waf1/Cip1). Accordingly, p53(-/-) cells exhibit reduced mitotic arrest and enhanced polyploidy upon survivin ablation as compared with their p53(+/+) counterparts. Partial reduction of the cytosolic pool of survivin by RNA interference sensitizes cells to ultraviolet B-mediated apoptosis and results in enhanced caspase-9 proteolytic cleavage, whereas complete ablation of cytosolic survivin causes loss of mitochondrial membrane potential and spontaneous apoptosis. These data demonstrate that survivin has separable checkpoint functions at multiple phases of mitosis and in the control of mitochondrial-dependent apoptosis.

Rights and Permissions

Citation: J Biol Chem. 2004 Jan 16;279(3):2077-84. Epub 2003 Oct 27. Link to article on publisher's site

DOI of Published Version

10.1074/jbc.M309479200

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of biological chemistry

PubMed ID

14581472