Many Pathways to Destruction: The Role of the Centrosome in, and Its Control by Regulated Proteolysis - The Centrosome - page 138

increase in centrosome amplification that phenocopied BRCA1 inactivation
(Starita et al. 2004 ). However, BRCA1 no doubt has other centrosomal functions.
For example, Nlp was recently identified in a yeast two-hybrid screen designed to
identify novel BRCA1 interacting proteins (Jin et al. 2009 ). Nlp and BRCA1
physically interact, and BRCA1 is required for the centrosomal localization of Nlp
(Jin et al. 2009 ). BRCA1 depletion leads to a loss of Nlp from centrosomes and to
enhanced Nlp degradation, presumably because BRCA1 negatively regulates Plk1,
which is elevated in BRCA1-depleted cells (Jin et al. 2009 ).
8.10 Ubiquitin-Independent Proteasomal Degradation
at Centrosomes
Interestingly, although the 26S proteasome is typically thought to be the active
proteasome species within the cell, the major cellular proteasome species is the
20S proteasome that makes up 1 % of total cellular protein [reviewed in (Zetter
and Mangold 2005 ). Moreover, it has recently been estimated that as much as
20 % of cellular protein can be degraded independently of ubiquitylation (Baugh
et al. 2009 ). While some disordered regions within proteins can allow direct access
to the 20S proteasome (Baugh et al. 2009 ; Tsvetkov et al. 2010 ), such as is the case
for p53 p21, c-fos and c-jun [reviewed in (Zetter and Mangold 2005 ; Tsvetkov
et al. 2010 ; Jariel-Encontre et al. 2008 )], ubiquitin-independent degradation can
also be conferred by cellular or viral factors. For example the 20S-dependent
degradation of p53 is regulated by NAD(P)H quinonie oxidoreductase (NQO1),
which prevents its association with the 20S proteasome, while pRb family mem-
bers and IjBa are targeted to the proteasome by the cytomegalovirus protein pp71
and the HTLV Tax protein, respectively, independently of ubiquitylation
[reviewed in (Zetter and Mangold 2005 ; Jariel-Encontre et al. 2008 )].
Relative to centrosomes, the most relevant ubiquitin-independent degradation
pathway is mediated by ornithine decarboxylase antizyme (OAZ). Initially char-
acterized as a regulator of polyamine biosynthesis, OAZ binds to ornithine
decarboxylase (ODC), and the ODC/OAZ complex is targeted to the proteasome
by binding to the same recognition site on the 19S regulatory subunit as ubiqui-
tylated proteins; however, ODC degradation occurs completely in the absence of
ubiquitylation [reviewed in (Zetter and Mangold 2005 )]. OAZ has a handful of
other substrates, including Smad1, SNIP1, Aurora A, and cyclin D1 [reviewed in
(Jariel-Encontre et al. 2008 )], many of which are also degraded via ubiquitin-
dependent routes. It was recently demonstrated that both OAZ and its antagonist
antizyme inhibitor (AZI) are found at centrosomes, and that OAZ activity
suppresses centrosome amplification (Mangold et al. 2008 ). This could not
be explained by the known OAZ substrates, and suggested that OAZ promoted the
degradation of some protein whose proper degradation restricted centrosome
duplication, and it was recently shown that OAZ regulates centrosome duplication