The first step in the action of a protein growth factor is its binding to a transmembrane receptor at

38 The first step in the action of a protein growth factor is its binding to a transmembrane receptor at

the surface of the target cell. The intracellular portion of the receptor then catalyzes the production of molecules that act as intracellular signals, relaying the stimulus to yet other molecules. The details of the initial steps in several of these signaling cascades have been well worked out for the surface of the target cell. The intracellular portion of the receptor then catalyzes the production of molecules that act as intracellular signals, relaying the stimulus to yet other molecules. The details of the initial steps in several of these signaling cascades have been well worked out for

We saw in Chapter 15 that growth-factor receptors activate intracellular phosphorylation cascades that lead to changes in gene expression. The genes that growth factors induce fall into two classes: early-response genes are induced within 15 minutes of growth factor treatment, and their induction does not require protein synthesis; delayed-response genes, by contrast, are not induced until at least 1 hour after growth factor treatment, and their induction requires protein synthesis. It seems that the delayed-response genes are induced by the products of the early- response genes, several of which are known to be gene regulatory proteins (Figure 17-44).

Both classes of genes are silent and not transcribed in cells in G 0 but are induced to high levels when growth factors are added to the medium. If the exposure to growth factors is then

maintained, the level of expression of the genes gradually falls back - for some genes apparently to zero, for certain others to a new non-zero steady value. Products of the latter class of genes are therefore present at a constant low level in steadily cycling cells (Figure17-45). Thus the transcription of these genes indicates the presence of growth factors in the medium, and a high level of expression indicates a sudden increase in growth factor concentration. The signals we get from our own senses (of smell, for example) behave in much the same way.

The best-studied early-response genes are the myc, fos, and jun proto-oncogenes. All three genes encode gene regulatory proteins that act as homo- or heterodimers (discussed in Chapter 9). When overexpressed or hyperactivated by mutation in certain types of cells, all of them can cause uncontrolled proliferation. There is evidence suggesting that mycin particular may have a critical role in the normal control of cell proliferation. Cells in which myc expression is specifically prevented will not divide even in the presence of growth factors. Conversely, cells in which myc

expression is specifically switched on independently of growth factors cannot enter G 0 , and if they are in G 0 when Myc protein is provided, they will leave G 0 and begin to divide even in the absence of growth factors - a behavior that ultimately causes them to undergo programmed cell death.

Cy c lin s a n d Cd k Are I n d u c e d b y Gro w t h Fa c t o r Aft e r a Lo n g

D e la y 34

The delayed-response genes do not begin to be transcribed until well after the addition of growth factor, and their transcription requires the products of the early-response genes such as myc. Among the products of the delayed-response genes are some of the essential components of the cell-cycle control system itself, including Cdk proteins and several cyclins, which, from the timing

of their expression, are suspected to be involved with Cdk proteins in driving the cells past the G 1 checkpoint, in initiating S phase, or both.

Thus one can tentatively trace a chain of stimulatory effects that leads from the binding of growth factor to the initiation of DNA replication. These stimulatory signals are thought to act by overcoming specific inhibitory devices that ensure that the cell refrains from proliferating in the absence of a positive signal to do so. The inhibitory devices are proteins encoded by the antiproliferation genes discussed earlier, which were originally discovered as tumor-suppressor genes in human cancers. The best-understood antiproliferation gene is the retinoblastoma gene.

Th e Re t in o b la s t o m a P ro t e in Ac t s t o Ho ld P ro life ra t io n in