Biology Reference
In-Depth Information
Fig. 14.1 Model for the
regulation of the centrosome
by BRCA1 and AURKA.
a Normal centrosome
duplication cycle (centrioles
are surrounded by the
pericentriolar material PCM).
In the presence of normal
levels of BRCA1 and
AURKA and during S-G2
phases of the cell cycle
BRCA1 ubiquitinates the
already duplicated
centrosomes to inhibit
reduplication. At M phase
AURKA phosphorylates
BRCA1 inhibiting its
ubiquitin ligase activity and
stimulating microtubule
nucleation. b Loss of
BRCA1: effects on the
centrosome. Loss of BRCA1
results in supernumerary
centrosomes during S phase.
These supernumerary
centrosomes may result in the
formation of mutipolar
spindles that would
ultimately cause abnormal
mitosis. c Model for the effect
of AURKA overexpression
on the centrosome.
Overexpression of AURKA
mimics the effects of loss of
BRCA1. Overexpressed
AURKA associates with the
centrosomes during S-G2
phase and blocks BRCA1
function when its activity is
most critical. In addition,
overexpressed AURKA
overrides the spindle
checkpoint contributing to an
abnormal mitosis
to breast cancer development (Ransburgh et al.
2010
). A similar assay that checks
the effects of the different mutants on the function of BRCA1 in the control of
centrosome number is currently being developed and results from both assays, the
HR and the centrosome assay, with genetic and clinical analysis of the point
mutants will be of great importance in counseling women carrying such mutations
and ultimately it will improve the prognosis of the disease.
