Biology Reference
In-Depth Information
in the promoter of the cyclin D1 gene, and sustained Erk activation leads to transcription
of cyclin.
23,24
The activation of Erk is usually driven by signals that arise fromgrowth factor receptors and
from integrin-type matrix receptors. The pathways from these receptors converge in such
a way that they effectively perform the Boolean 'AND' operation, at least for physiological
levels of ligand. In at least some cells, integrin-derived signals operate via small GTPases of
the Rho family, which synergizes with the signalling pathway upstream of Erk to ensure
sustained Erk activation.
22
Cells will therefore respond to physiological levels of growth
factors only if they are sitting on the correct matrix, which is an important error-checking
mechanism in development and in adult life.
As proliferative signals can act by increasing production of cyclin-cdk complexes capable
of inactivating Rb, thus ensuring progression of the cell cycle, anti-proliferative signals can
act by inhibiting these cyclin-cdk complexes. For many cell types, TGF
b
is an example of
such an anti-proliferative signal. The TGF
signalling pathway activates transcription
of the p15
INK4B
gene, which encodes a protein that can bind the cyclin-dependent kin-
ase, cdk4. The p15
INK4B
protein competes for cdk4 with a complex of cdk4, cyclinD1 and
p27
kip1
; the effect of increasing the amount of p15
INK4B
in the cell is therefore to liberate
p27
kip1
from this complex. Once free, the p27
kip1
inhibits the activation of cdk2 by cyclin
E and therefore blocks progress through the restriction point
26
e
29
(
Figure 22.8
).
In practice, more than one pathway will converge on the restriction point and cells inside
developing embryos will use all of them to integrate information about the concentration of
mitogenic and anti-proliferative signalling molecules in their vicinity with information about
cell-cell contacts and cell matrix contacts, and about their own size and differentiation state.
Detailed discussion about these pathways and how they converge can be found in a number
of excellent reviews that go far beyond what can be described here.
22,25
The key point, as far
b
FIGURE 22.8
Coupling between extracellular signals and the restriction point of animal cell cycles. In this
example, the anti-mitotic signalling molecule TGF
causes the transcription of a protein that titrates cdk4 away from
a cdk4-cyclinD-p27
kip1
complex, and this liberates p27
kip1
b
from that complex so that it can inhibit activation of
cdk2/cyclinE.
