Growth Factors

is the term for a class of gene products that play important roles in the regulation of cell division and tissue proliferation. Each growth factor has a specific cell-surface receptor. Binding of the growth factor to the receptor initiates or, in some cases, blocks cell division. Most growth factors regulate only certain types of cells and tissues.

Control of Cell Division is an active process involving both stimulation and inhibition (by antagonists). Mitosis, for example, will not occur in the presence of active inhibition and the absence of stimulation.

Growth factors regulate defined phases of the cell cycle. The two most important phases of the cell cycle are the transition from:

G₀-----------> G₁
and

G₁-----------> S.

The transition from G₀ to G₁ is controlled by growth factors for:

• skin cells (epidermal growth factor, EGF)
• nerve cells (nerve growth factor, NGF)
• connective tissue or mesenchymal cells (fibroblast growth factor, FGF)
• thrombus-forming cells that line blood vessels (platelet- derived growth factor, PDGF)

An important growth factor regulating the transition from G1 to S is insulin-like growth factor, IGF-1.

The stimulating effect of these growth factors can be opposed by such antagonists as:

• transforming growth factor-beta (TGF-beta)
• tumor necrosis factor (TNF).

Activation of a Growth Factor Receptor

A growth factor receptor is activated by binding to a specific growth at the cell's surface. The activated receptor, in turn, activates an intracellular protein (i.e., "substrate protein"). A receptor such as platelet-derived growth factor (PDGF) can stimulate a number of substrates including Ras protein, the Src protein (the name is derived from the tumor, a sarcoma, in which it was first found), or phospholipase C, a signal transmitter.

AN EXAMPLE... RAS
PDGF binds to its receptor ----> Ras protein is activated ---- >
Ras triggers a short, time-limited signal ----> cell division is initiated.

Then, Ras is inactivated by GTPase activation protein (GAP).

If a gene mutation is present in either Ras or GAP, the time-limited aspect of the cell-stimulating signals may be lost...resulting in uncontrolled cell division which can lead to tumor formation.

Types of Growth Factors

There are Four Classes of Growth Factors:

• Class I comprises growth factors interacting with specific receptors at the cell surface and includes epidermal growth factor (EGF), growth hormone (somatotropin), and platelet- derived growth factor (PDGF).
• Class II are cell surface hormone receptors, frequently protein tyrosine kinases in the cytoplasmic domains of the receptor, as for EGF and PDGF.
• Class III consists of a large group of intracellular signal transmitters, or transducers, belonging to different families, e.g., Ras proteins and protein kinases such as Src.
• Class IV are nuclear transcription factors (proteins that bind to specific DNA segments such as promoters, resulting either in initiation of mRNA transcription or suppression of transcription). Initiators of DNA transcription include fos, myc, myb, and N-myc. Suppressors of cell division are such proteins as p53 and the retinoblastoma gene product.