Biology Reference
In-Depth Information
for the inhibitory phosphorylation of Cdk1 and Cdk2, and, therefore, it is the
complementary counterpart to the Cdk/cyclin complex-activating protein
phosphatases Cdc25A, B, and C, which remove these phosphorylations.
108-111
Like its upstream kinases ATR and Chk1, Wee1 is essential for mammalian
development, and its conditional deletion in mice leads to growth defects and
apoptosis due to aneuploidy and DNA damage.
112
Several studies using knock-
down of Wee1
113,114
or Wee1-specific inhibitors indicate that loss of Wee1
function is a promising strategy to abrogate the G2/M arrest in combination
with DNA-damaging therapy.
Various compounds that inhibit Wee1 have recently been described in the
literature, including PD0166285
115-117
and MK-1775, each of which shows a
different cross-reactivity to other kinases (reviewed in Ref.
118
). The more
selective compound MK-1775 has successfully been used in combination with
DNA-damaging agents in mouse xenograf models.
119-122
Importantly, the
efficiency of checkpoint abrogation appears to correlate with
p53
deficiency
in many of the tumor types and human cell lines tested. Its clinical application
is currently being tested in phase I and phase II studies. Preliminary results
show good tolerability and promising anticancer activity.
123
V. Potential for Future Therapies
A. Novel Players in the Genotoxic Stress Response:
Posttranscriptional Regulation of Selective mRNAs
Upon DNA Damage
Many of the changes in cellular mechanisms that occur upon DNA damage,
such as delay in cell cycle progression, activation and recruitment of the DNA
damage repair machinery, and others, can be explained by posttranslational
modifications of proteins within the DNA damage signaling network through
phosphorylation, ubiquitinylation, or sumoylation.
23
Recently, however, the
posttranslational control of mRNA stability, splicing, and translation in response
to genotoxic stress has emerged as an additional aspect of regulation in the
cellular DNA damage response.
DNA damage triggers a transient repression of transcriptional activity in
eukaryotic cells.
124,125
Despite this transcriptional block, cells up- and down-
regulate a large portion of their mRNAs following exposure to a variety of
DNA-damaging agents.
126,127
A major contributor to these changes in gene
expression is the posttranscriptional regulation of mRNA levels. Global analysis
of changes in mRNA levels upon UV irradiation of lung carcinoma cells, for
example, showed that mRNA turnover is responsible for more than half of the
observed regulatory events.
128
Stability, splicing, and translation of mRNA are
