Mitogens and the Cell Cycle

Unicellular organisms, such as bacteria, divide when there are enough nutrients in the environment.

However, in multicellular organisms, most cells remain in G0, or the non-dividing phase, until cell division is triggered by extracellular signal molecules, called 'mitogens’.

Mitogens are usually small proteins or peptides secreted in response to different stimuli, such as tissue injury, infection, or a routine regeneration.

For instance, in the case of tissue injury, specialized cells secrete a mitogen called Platelet-derived growth factor or PDGF.

Such mitogens can bind to the extracellular domain of tyrosine kinase receptors such as PDGF-Receptor, inducing receptor dimerization and autophosphorylation of its intracellular domains. This allows phosphorylation and activation of the downstream intracellular molecules that are involved in multiple signaling pathways.

The mitogen-activated protein kinase or MAP kinase cascades are a type of signaling pathway induced by mitogen-receptor binding. This pathway starts with the activation of the small membrane bound GTPase named Ras by the receptor.

Next, active Ras triggers the MAP kinase cascade which includes a series of kinase proteins. In a chain of phosphorylation reactions, first MAP3 kinase activates MAP2 kinase, and then finally MAP kinase.

Active MAPK then translocates into the nucleus where it activates regulatory transcription factors, including Myc.

Myc increases the expression of G1 cyclins that partner with cyclin-dependent kinases or Cdks.

The G1 cyclin-Cdk complex phosphorylate Rb - a tumor suppressor protein - freeing the bound gene regulatory factor-E2F. Active E2F then binds to a specific DNA sequence and triggers transcription of cell cycle genes that encode several proteins necessary for cell division.

As the mitogenic stimuli recede, such as during the healing of injured tissues, Rb protein interacts with E2F inhibiting its activity, thus, preventing excessive cell growth.