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was subsequently shown to initiate specifically at centrosomes in both fruit fly
embryos (Huang and Raff 1999 ; Raff et al. 2002 ) and human cells (Clute and Pines
1999 ). In flies it was shown that this spatial destruction of cyclin B is regulated
by the distribution of Vihar, an E2 enzyme responsible for ubiquitylation of
APC/C substrates (Mathe et al. 2004 ). Vihar localizes to centrosomes and is itself
an APC/C substrate that disappears first from centrosomes. Interestingly, Vihar
degradation leads to the auto-deactivation of APC/C at centrosomes, releasing the
APC/C from centrosomes to initiate the subsequent waves of cyclin B degradation
elsewhere along the spindle and in the cell (Mathe et al. 2004 ). The human
ortholog of Vihar, UbcH10, also localizes to centrosomes and its overexpression
leads to precocious degradation of cyclin B, centriole amplification, and aneu-
ploidy (van Ree et al. 2010 ). UbcH10 is also elevated in human tumors, and its
overexpression in mice promotes tumor formation (van Ree et al. 2010 ).
Several other centrosome-associated APC/C substrates have been described,
including L2DTL, the human ortholog of fly lethal (2) denticleless (Pan et al.
2006 ), microtubule associated protein CKAP2 (Seki and Fang 2007 ), Ninein-like
protein (Nlp) (Wang and Zhan 2007 ), hSas6 (Strnad et al. 2007 ), and Nek2 (Hames
et al. 2001 , 2005 ). Nlp regulates centrosome maturation, and is critical for chro-
mosome segregation and cytokinesis. Nlp is an APC/C substrate whose levels peak
at G2/M due to the combined activities of Cdc20 and Cdh1 (Wang and Zhan
2007 ). However, Plk1 phosphorylation prevents the interaction of Nlp with
c-Tubulin and leads to the release of Nlp from centrosomes, which is required for
proper centrosome maturation and spindle assembly (Casenghi et al. 2003 ), sug-
gesting that cytoplasmic Nlp may be the relevant APC/C substrate. Similarly,
hSas6 is targeted for APC/C-dependent degradation by binding to Cdh1 at G2/M
(Strnad et al. 2007 ), but because hSas6 can only be incorporated into centrioles at
G1/S this degradation must largely occur in the cytoplasm. Regardless, increasing
hSas6 levels causes centriole overproduction (Strnad et al. 2007 ), and the Cdh1-
dependent degradation of hSas6 at G2/M ensures that its levels are low in the
subsequent G1/S when procentrioles form. In contrast, the degradation of Nek2
has been shown to occur explicitly at centrosomes. Nek2A is targeted for
destruction through its cyclin A-type D-box in early mitosis (Hames et al. 2001 ).
Nek2 is targeted to centrosomes via centriolar satellites, but once at centrosomes is
rapidly exchanged via APC/C-dependent degradation (Hames et al. 2005 ). That
Nek2A degradation occurs at centrosomes was demonstrated using FRAP analysis,
which showed that either proteasome inhibition or expression of non-degradable
Nek2 mutants greatly reduced the rate of recovery of GFP-Nek2A at centrosomes
(Hames et al. 2005 ); had Nek2A been released from centrosomes and degraded in
the cytoplasm, the recovery would not have been expected to change in response to
preventing Nek2A degradation.
In addition to APC/C-dependent regulation described above in proliferating
cells, the APC/C has functions at centrosomes in differentiated cells as well. Cdc20
is enriched at the centrosomes in neurons, and its RNAi-mediated depletion
impairs the formation of dendritic arbors (Kim et al. 2009 ). The relevant Cdc20
substrate was shown to be Id1, and the APC-dependent degradation of Id1 at
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