Deregulation of the Centrosome Cycle in Cancer

G1/S and G2/M checkpoints enforce the orderly completion of cell cycle events, and when triggered, they inhibit the formation and/or activation ofCdks and thereby induce cell cycle arrest (63,64). Cell cycle checkpoints operate through the action tumor suppressor proteins p53 and Rb, and their downstream activation target Cdk2. Interestingly both p53 and Cdk2 may also physically reside at the centrosome, albeit only transiently (65,66). The physical presence ofkey proteins involved in checkpoint control at the centrosome has led to the suggestion that the centrosome itselfmay provide an important structural context for coordinating cell cycle regulation (56, 65-70).

Centrosome abnormalities in cancer are correlated with loss of p53 function in carcinomas of the breast, head and neck, and prostate, and in neuroectodermal tumors (14, 34, 71). In tumors that retained wild-type p53, amplified centrosomes were frequently associated with overexpression of MDM2, which abrogates p53 function by promoting its degradation (71). Furthermore, gain-of-function p53 mutations and p53 null mice can result in deregulation of centrosome duplication leading to the generation of functionally amplified centrosomes and aberrant mitoses (72-74). Interestingly, in some cancers p53 mutations and cyclin E overexpression may act synergistically since together they increased the frequency of centrosome defects in cultured cells and in mouse models (75).

Centrosome homeostasis is controlled at the G1/S and G2/M checkpoints (Figure 1) through transcriptional regulation by p53 of several downstream targets including the Cdk inhibitor p21/waf1 (76, 77). As discussed earlier, p21/wafl blocks centrosome duplication through inhibition of Cdk2/cyclin E activity. This conclusion is supported by experiments in which anti-sense targeting ofp21/wafl in human cell lines resulted in endoreduplication and centrosome amplification (78).

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Figure 1. (a) Model illustrating the centrosome and DNA cycles in cells with normal and with defective checkpoint controls as discussed in the text. (b) Electron micrograph of an amplified centrosome with five centrioles from a human mammary tumor (courtesy of Wilma Lingle, Mayo Clinic).

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Figure 1. (a) Model illustrating the centrosome and DNA cycles in cells with normal and with defective checkpoint controls as discussed in the text. (b) Electron micrograph of an amplified centrosome with five centrioles from a human mammary tumor (courtesy of Wilma Lingle, Mayo Clinic).

embryonic fibroblasts re-established centrosome homeostasis, overexpression of p21/waf1 only partially restored control of centrosome duplication in p53-null fibroblasts, suggesting that alternative downstream p53 targets may also be involved in the regulation of centrosome homeostasis (79, 80). In this regard, GADD45, another downstream product of the p53 pathway, has been implicated in activation of the G2/M checkpoint and regulation of the centrosome cycle (81-83). Alternative mechanisms, independent of p53 function, may also lead to deregulation of centrosome homeostasis (25, 26, 84, 85). For example high-risk human papillomavirus (HPV) v-oncogenes, E6 and E7, have been implicated in the induction of centrosome amplification in human cell lines (86). HPV E6 and E7 interfere with centrosome homeostasis by targeting different pathways. Whereas E6 may operate through inactivation of p53 function resulting in accumulation of excess centrosomes by failure of the G2/M checkpoint leading to defects in cytokinesis, E7 may lead to centrosome amplification through inactivation ofthe Rb and G1/S checkpoint resulting in abnormal centrosome duplication (86). In addition, as discussed above, centrosome amplification can be induced by overexpression of the centrosome kinase BTAK/STK15 (8), mutations in the BRCA1 and BRCA2 tumor suppressor genes (87-92) or by over-expression of the PCM structural protein pericentrin (30). Thus, centrosome defects and consequent genomic instability may result from inactivation of cell cycle checkpoints, inappropriate activation of key centrosome kinases, or alterations in structural proteins of the centrosome itself. These observations suggest several regulatory pathways operate in parallel to ensure linkage between the DNA, cell, and centrosome cycles. In the development of cancer, centrosome defects may result from an imbalance between negative and positive regulators that converge on G1/S and G2/M checkpoints, or directly on components of the centrosome itself.

Interestingly, while introduction of wild-type p53 into mouse

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