Biology Reference
In-Depth Information
Some cyclins contain sequences that target them and their CDK partner to
specific subcellular localisations. For example, cyclin B1 encodes a cytoplasmic
retention sequence whose phosphorylation triggers the nuclear localisation of
CDK1-cyclin B1. This is essential for phosphorylation of nuclear lamina A which
triggers the breakdown of the nuclear envelope in prophase (Li et al.
1997
).
Recently, the A and E type cyclins have been found to encode centrosome
localisation sequences that target these proteins to the centrosome (Matsumoto and
Maller
2004
; Pascreau et al.
2010
).
11.2 CDK Control of the Centrosome
Each cell inherits a single centrosome at the end of cell division and a single copy
of DNA. In order for accurate chromosome segregation during the next cell
division, both the chromosomal DNA and the centrosome must replicate, once.
Centrosome replication thus commences with DNA replication at the G1-S phase
transition. CDK2-cyclin E in the nucleus initiates DNA replication through
phosphorylation of the Retinoblastoma (Rb) protein and activation of the E2F
transcription factor (Stevaux and Dyson
2002
). Similarly, CDK2-cyclin E at the
centrosome is believed to initiate centrosome replication by phosphorylation of its
centrosome substrates, such as nucleophosmin (Hinchcliffe and Sluder
2002
).
11.2.1 CDK2-Cyclin E/Cyclin A Control of Centrosome
Replication
The first step in centriole replication is centriole disorientation—the loss of
orthogonal association between the mother and daughter centrioles—in late G1
phase. This process was shown to be dependent on CDK2-cyclin E. Centriole
disorientation was found to occur in late G1 phase in isolated mammalian cells that
were incubated with control Xenopus egg extracts containing normal CDK2-cyclin
E activity but not in extracts that had been treated with the CDK2-cyclin E
inhibitors p21 or p27 (Lacey et al.
1999
).
Centriole disorientation is followed in early S phase, by the appearance of small
procentriole structures oriented at right angles to the original centrioles, that
elongate during S phase. Under normal cell cycle conditions, only one procentriole
forms perpendicular to each existing centriole (Tsou and Stearns
2006
). However,
if cells are arrested in S phase for prolonged periods, by inhibitors of DNA or
protein synthesis for example, multiple procentrioles can form next to each
existing centriole through repeated cycles of centrosome replication (Balczon et al.
1995
). This experimental uncoupling of centrosome replication from DNA repli-
cation was exploited in a series of reports in 1999 that demonstrated that the
