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Research Article |
1 Boyer Center for Molecular Medicine, Department of Pathology, Yale University
School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA
2 NOVUS Biologicals, Inc. P.O. Box 802, Littleton, CO 80160, USA
3 Vita-Salute University School of Medicine, San Raffaele Scientific Institute,
Via Olgettina 58, Milano, 20132, Italy
Author for correspondence (e-mail: dario.altieri{at}yale.edu)
Accepted 23 October 2001
Survivin is a member of the inhibitor of apoptosis gene family that has
been implicated in both apoptosis inhibition and regulation of mitosis.
However, the subcellular distribution of survivin has been controversial and
variously described as a microtubule-associated protein or chromosomal
passenger protein. Here, we show that antibodies directed to the survivin
sequence Ala3-Ile19 exclusively recognized a nuclear
pool of survivin that segregated with nucleoplasmic proteins, but not with
outer nuclear matrix or nuclear matrix proteins. By immunofluorescence,
nuclear survivin localized to kinetochores of metaphase chromosomes, and to
the central spindle midzone at anaphase. However, antibodies to
Cys57-Trp67 identified a cytosolic pool of survivin,
which associated with interphase microtubules, centrosomes, spindle poles and
mitotic spindle microtubules at metaphase and anaphase. Polyclonal antibodies
recognizing survivin epitopes Ala3-Ile19,
Met38-Thr48, Pro47-Phe58 and
Cys57-Trp67 identified both survivin pools within the
same mitotic cell. A ratio of 
1:6 for nuclear versus cytosolic survivin
was obtained by quantitative subcellular fractionation. In synchronized
cultures, cytosolic survivin abruptly increased at mitosis, physically
associated with p34cdc2, and was phosphorylated by
p34cdc2 on Thr34, in vivo. By contrast, nuclear survivin
began to accumulate in S phase, was not complexed with p34cdc2 and
was not phosphorylated on Thr34. Intracellular loading of a
polyclonal antibody to survivin caused microtubule defects and resulted in
formation of multipolar mitotic spindles, but did not interfere with
cytokinesis. These data demonstrate that although both reported localizations
of survivin exist in mitotic cells, the preponderant survivin pool is
associated with microtubules and participates in the assembly of a bipolar
mitotic spindle.
Key words: Survivin, Microtubules, Mitotic spindle, Kinetochore, p34cdc2
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