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A more recent version of this article appeared on August 1, 2004
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Submitted on November 7, 2003
Revised on April 29, 2004
Accepted on May 3, 2004
tubulin complexes by pericentrin controls spindle organization and mitotic entry
, , , *
Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605
Monitoring Editor: Tim Stearns
Microtubule nucleation is the best known function of centrosomes. Centrosomal microtubule nucleation is mediated primarily by 
tubulin ring complexes ( TuRCs). However, little is known about the molecules that anchor these complexes to centrosomes. In this study we show that the centrosomal coiled-coil protein pericentrin anchors TuRCs at spindle poles through an interaction with tubulin complex proteins 2 and 3 (GCP2, 3). Pericentrin silencing by small interfering RNAs in somatic cells disrupted tubulin localization and spindle organization in mitosis but had no effect on tubulin localization or microtubule organization in interphase cells. Similarly, overexpression of the GCP2/3 binding domain of pericentrin disrupted the endogenous pericentrin- TuRC interaction and perturbed astral microtubules and spindle bipolarity. When added to Xenopus mitotic extracts, this domain uncoupled TuRCs from centrosomes, inhibited microtubule aster assembly and induced rapid disassembly of preassembled asters. All phenotypes were significantly reduced in a pericentrin mutant with diminished GCP2/3 binding, and were specific for mitotic centrosomal asters as we observed little effect on interphase asters or on asters assembled by the Ran-mediated centrosome-independent pathway. Additionally, pericentrin silencing or overexpression induced G2/antephase arrest followed by apoptosis in many but not all cell types. We conclude that pericentrin anchoring of tubulin complexes at centrosomes in mitotic cells is required for proper spindle organization and that loss of this anchoring mechanism elicits a checkpoint response that prevents mitotic entry and triggers apoptotic cell death.
*Corresponding author. E-mail address: stephen.doxsey{at}umassmed.edu
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