Growth was initially defined as the chemical compounds that can affect the growth of the cell, recent studies have developed a better understanding that has led to expansion of the definition. Growth factors are now described as gene products that can promote or inhibit mitosis or affect cellular differentiation. Growth hormones are generally steroid hormones or secreted proteins. It acts on cells to ultimately alter the genetic expression of the protein to regulate the cell cycle progression. It is achieved by binding of growth factor to the growth factor receptor. This receptor activates a signaling cascade that leads to the transduction of the signal to the interior of the cell, which ultimately generates a response by inhibiting or activating transcription and translation of the gene.
An important point is that for a cell to divide and continue its cell cycle progression, growth factors are required, it is the binding of growth factors that allows the cell to move from the G0 phase to continue the cell cycle, thus it acts as a positive regulator of the cell division. In cancerous cells, the cells do not require growth factors to continue the cell cycle, thus leading to amplified cell division which leads to tumor formation.
Growth Factor and Control of Cell Growth.
Cell growth can be referred to as cell division. Cell division is an active process that requires activation and inhibition of cell cycle proteins. Growth regulates the transition of the cell through two important checkpoints they are,
G0 -----------> G1
G1 -----------> S
These checkpoints are called DNA damage checkpoints, cells will not cross this checkpoint or in other words, cells are arrested if any DNA damage is found, in case of DNA damage, the genome is repaired by the cell and then proceeds to cell division. The cell cycle will not continue in the presence of active inhibition and the absence of stimulation. Growth factors provide active stimulation. The transition from G0 to G1 is controlled by growth factors in the following cells.
A skin cell, epidermal growth factor (EGF) is the growth factor that regulates transition.
In connective tissue, the transition of such cells is regulated by fibroblast growth factor (FGF).
Mesenchymal cells are also regulated by fibroblast growth factor.
Nerve cells are regulated by the nerve growth factor (NGF).
Thrombus forming cell (platelet) regulation of types of cell are controlled by the platelet derived growth factor (PDGF).
Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis, the process of formation of the blood vessels.
G1 to S phase transition is regulated by an important class of growth factors known as insulin-like growth factors. These biologically active compounds are also known as somatomedin, it stimulates cell growth by acting on the pituitary gland, which releases the growth hormone. Growth hormones do not directly act on cells to stimulate cell division, rather they increase the metabolic rate of the cell.
The Antagonist of Growth Factor
The inhibitory molecules are also present in the cell, these act as an antagonist to the growth factors, that is they halt the cell cycle progression. These molecules are activated in case DNA damage is sensed. Antagonists are also known as anti mitogen. The two most widely studied anti mitogen are Tumor necrosis factor (TNF) and transforming growth factor-beta (TGF- beta).
Transforming growth factor-beta is the potent anti mitogen that inhibits cell cycle progression in the G1 stage. They block the activation of CDKs of this phase, this results in the prevention of pRb phosphorylation and S phase entry.
Tumor necrosis factor inhibits the cell cycle progression by inhibiting the progression to the S phase; it also induces apoptosis by blocking CDK1 cycling of the Mitotic phase.
Mechanism of Action of Growth Factor
Growth factor works by intracellular signaling, every growth factor has a specific receptor present on the plasma membrane of a cell. Growth factors that are of steroidal origin such as steroid hormone (glucocorticoid, estrogen) have the intracellular receptor, that is they have a receptor on the nuclear membrane of the cell. Such a type of receptor is known as the nuclear receptor. Growth hormone binds to the receptor undergoes a conformational change, it then activates a cascade of protein by phosphorylation, dephosphorylation. This leads to alteration in the expression of genes that are involved in cell division. Genes that code for cyclin, CDK, or inhibitory protein are activated or inactivated as per the need of the cell.
Example of Sequential Action of Growth Factor via RAS-MAPK Pathway
GF- receptor association (somatomedin- receptor)
Conformational change in the receptor undergoes dimerization
Autophosphorylation of receptor
Binding of grb-2 protein
Binding of SOS which as GEF (guanine exchange factor)
Binding RAS (G-protein)
Binding of RAF
Phosphorylation of RAF
Addition and phosphorylation of MEK (Mitogen extracellular regulated kinase)
Addition and phosphorylation of ERK (extracellular regulated kinase)
Phosphorylation of transcription factor ELK, which promotes transcription and expression of CDK 4 and CDK 2 (involved in early and late G1 stage)
These phosphorylated retinoblastoma proteins, which is the inhibitor of this stage, thus inactivating it.
Types of Growth Factors
There are four kinds of growth factors they are known as, class I, class II, class III and, class IV.
Class I- This class includes growth factors that interact with the specific receptor present on the plasma membrane of the cell. It includes somatotropin, also known as growth hormone, epidermal growth factor and Platelet - Derived Growth Factor (PDGF).
Class II- This class includes GF that interacts with a receptor that is a cell surface hormone receptor having tyrosine kinase activity in their cytoplasmic domain. An example of this class is the insulin-like growth factor.
Class III- It includes large group intracellular signal transmitters such as ras and src protein.
Class IV- This class includes intracellular nuclear transcription factors, they work by altering the expression of the gene, an example of such molecules acting as initiators are fos, myc, myb, and N-myc. Example of suppressors of cell division is as p53 and the retinoblastoma.