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Unformatted text preview: yed early genes, including CCND, are induced. The Cyclin DCDK4/6 complex then initiates RB phosphorylation, which activates the E2F family
of transcription factors and induces expression of target genes, including CCNE
(encoding cyclin E). The Cyclin E-CDK2 complex further phosphorylates RB and
activates the E2F family. This positive feed back loop drives the cells to S phase entry
Another possible downstream effector of RAS-induced cell cycle changes is p27Kip1
(p27). Although RAS leads to an increased level and CDK-binding of cyclin D1 in
quiescent cells, the CDK-complexes formed, are inactive in many cases and unable to
promote cell cycle progression due to bound p27. Only after growth factor 21 stimulation, p27 is downregulated and S-phase entry occurs. Similarly, activation of
MEK in serum-starved cells increases the amount of inactive CDK/cyclin D
complexes, since p27 is not degraded as it is in response to serum though contrasting
results have also been obtained. Although RAS is unable to repress p27 levels in the
quiescent state, the RAS pathway seems to be required for p27 downregulation by
serum (91). The RAF-MEK-ERK pathway is perhaps, the best characterized effector
pathway causing the downregulation of p27 by RAS. Moreover, inhibition of PI3K
blocks growth factor-induced downregulation of p27, suggesting a role also for this
effector in RAS-mediated p27 downregulation (89). RAS and cell invasion
Oncogenic RAS proteins stimulate a number of effector pathways that end in the
transcriptional activation of genes, which control migration, invasion and
angiogenesis. Several ERK substrates have been implicated in cell migration, such as
myosin light chain kinase (MLCK), calpain proteases, focal adhesion kinase (FAK)
and paxillin (92). There are also some reports that show a synergistic interaction
between integrin-mediated cell adhesion and ERK activation in cell migration (93).
Since integrins are thought to regulate RAS activation via focal adhesion kinase
(FAK), it shows a feedback loop in which mutant RAS leads to its own activation.
RAS deregulation of R...
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