Biology Reference
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as morphogenesis is concerned, is that cell proliferation is a regulated process and that each
cell decides for itself, when it is at the restriction point, whether or not to divide. That deci-
sion depends on the signals that are present in its immediate environment.
LOCAL CONTROL OF CELL PROLIFERATION
The cells' ability to integrate diffusible and local signals to determine whether they should
cycle allows them to regulate their proliferation according to a balance of local and 'global'
controls. A local reason to proliferate might be the need to replace a dead cell or to seal up
a hole, while a global reason may be to increase the size of a complete organ or embryo.
An example of strictly local control that has been studied for many years gives rise to the
phenomenon of contact inhibition of proliferation. Contact inhibition of proliferation
prevents cells that are completely surrounded by neighbours from proliferating, but allows
those that make contact with free space to proliferate to fill that space. The phenomenon is
reminiscent, in its simplicity, of the 'Game of Life' introduced in Chapter 2, and it is an effi-
cient way to target proliferation so that spaces are filled but cells do not pile up where there is
no more space. Its failure is one of the hallmarks of neoplastic transformation.
Contact inhibition of proliferation is still not completely understood, but the components
that have been identified point to a link between adhesion systems and the cell cycle. In some
cells, contact inhibition seems to act by modulating the activation of Erk MAP-kinase. For
example, the activity of Erk, and hence the expression of cyclin D, in the MDCK renal epithe-
lial cell line is higher when cells have free space than when they are crowded. Destruction of
cell-cell junctions, using trypsin, restores the Erk activity to that of uncrowded cells, but it
falls away again when junctions are re-established. 30 Treatment of the cells with sufficiently
high concentrations of the growth factor, HGF, does succeed in activating Erk and cyclin D
expression. In both MDCK kidney cells and MCF10 mammary cells, the ability of cell-cell
contact to inhibit growth in response to epidermal growth factor (EGF) depends on the stiff-
ness of the cells' substrate, with stiffer substrates weakening the effect of contact inhibition. 31
Contact inhibition is therefore not an absolute state in these cells, and it can be over ridden.
This probably reflects the situation in a real embryo; intact epithelia do, after all, grow by cell
proliferation so it is clear that contact inhibition must be capable of being over ruled in
a controlled manner.
The link between cadherins and Erk is not yet clear. It is known that the simple act of
E-cadherin binding to its ligand, even if the ligand is on an artificial microsphere, is enough
to induce contact inhibition. 32 In at least some cells the ability of E-cadherin to inhibit
Erk depends on the cells having a functional PI-3-kinase pathway, and constitutively active
mutants of Akt, a component of the PI-3-kinase pathway, result in the constitutive suppres-
sion of Erk. 33 PI-3-kinase is also seen to be located at the inner face of cell junctions on
E-cadherin binding. There is the potential for a link via the signal transduction protein
IQGAP1, which binds to Erk and inhibits it. 34 IQGAP1 also binds E-cadherin, and it is
possible that the state of E-cadherin modulates competition between these two proteins
and thus regulates Erk activity.
Contact inhibition can also occur via the proliferation inhibitor p27 kip1 , the levels of
which are elevated when cells make contact with each other in culture. 35,36
In at least
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