Biology Reference
In-Depth Information
There are, in principle, two main ways in which the proportions might be controlled. One
method would be to rely on cells maintaining an intrinsic proliferation rate, characteristic
of their state of differentiation, that is correct for the final tissue. This method would have
the disadvantage that small errors may have serious consequences for the final ratio, because
growth is exponential. The other, better, method would be for the proliferation of each cell
type to be controlled by population-dependent signals that emanate from the other
cell type(s) so that growth of each population is balanced. Signals that emanate from one
cell type and act on another are described as 'paracrine'.
The tissues of most organs consist of a mixture of epithelial and mesenchymal cells that
perform the main functions of the tissue, and vascular endothelia that brings blood to the
tissue to sustain it. The ratio of endothelia to the other cells is important; too little, and the
other cells will be hypoxic, undernourished and poisoned by their own waste products;
too much, and the tissue becomes dominated by endothelia that get in the way of other func-
tions. At least some of the signalling pathways that balance the growth of endothelia and
other cells have been identified. Proliferation of tissue cells such as fibroblasts is controlled
in part by the availability of oxygen. Cells cultured in hypoxic conditions fail to pass the
G1 restriction point.
45,46
Oxygen is sensed by the protein hypoxia inducible factor 1
a
(HIF1
). Under normal oxygen conditions, this molecule is rapidly ubiquitinated and
destroyed so that cellular concentrations remain low. In low oxygen, ubiquitination fails
and HIF1
a
levels rise.
47,48
HIF1
is a transcription factor which increases the expression of
the cycle inhibitor p27
kip1
and thus blocks the activity of cyclin-E/cdk2 complexes.
49
Without
cyclinE/cdk2 function, Rb remains unphosphorylated and it will inhibit the E2F-dependent
transcription of genes required for progression into S phase (see
Figure 22.8
). In monkey
kidney cells, at least, this repression is deepened by an up-regulation of a phosphatase
that returns any Rb that has been phosphorylated to its unphosphorylated, E2F-inhibiting
state.
50
Hypoxia caused by a shortage of functional vascular endothelium therefore arrests prolif-
eration in tissues, so that they will not outgrow their blood supply. Amongst the genes regu-
lated by HIF1
a
a
is one that encodes the extracellular signalling molecule, vascular endothelial
growth factor (VEGF).
51,52
Cells that are therefore arrested by hypoxia produce VEGF and
secrete it into their environment. Vascular endothelia bear the VEGF receptor tyrosine kinase,
Flk-1, and VEGF acts as a powerful mitogen for endothelial cells, acting via Erk and also other
signal transduction pathways such as PI-3-kinase.
53,54
The proliferation of endothelial cells is
therefore limited by the extent of VEGF production by the cells of the tissue, which is in turn
limited by the amount of oxygen made available by the endothelial system (
Figure 22.10
).
The system described above is especially well studied, because developing an ability to
modulate the expansion of blood vessels pharmacologically is a promising strategy for
restricting the growth of tumours.
55
It is, however, unusual in using oxygen as one of the
signals and in most cases peptide growth factors mediate communication in both directions.
In the developing kidney, for example, peptide growth factors are used to balance the growth
of the epithelial collecting duct tree with that of the mesenchyme into which it expands (the
development of the kidney is described further in Chapter 20). Expansion of the collecting
duct system depends on mesenchyme-derived growth factors such as GDNF and HGF, while
survival and expansion of the mesenchyme depends on epithelium-derived growth factors
such as FGF2 and TGF
a
a
. The proliferation of the two types of cells cannot, therefore, become
