Inositol lipids and DNA replication.

Control of DNA synthesis by growth factors seems to depend upon the generation of intracellular mitogenic signals, which are responsible for initiating the sequence of events leading to the onset of DNA synthesis. Many growth factors have tyrosine kinase activity suggesting the proteins phosphorylated on tyrosine might be likely candidates as intracellular signals. Other candidates are the calcium and hydrogen ions whose concentrations change dramatically during the action of most growth factors, many of which also stimulate the hydrolysis of inositol lipids. In particular, certain growth factors stimulate the hydrolysis of phosphatidylinositol 4,5-bisphosphate to give the two second messengers diacylglycerol and inositol 1,4,5-trisphosphate (Ins1,4,5P3). The former stimulates protein kinase C, which is responsible for increasing intracellular pH by switching on an Na+-H+ exchanger. The water-soluble Ins1,4,5P3 released to the cytosol can be metabolized along two separate pathways: it can either be dephosphorylated to free inositol or it can be converted into additional inositol polyphosphates such as Ins1,3,4,5P4 and Ins1,3,4P3. These inositol phosphates seem to play a key role in regulating intracellular calcium, with Ins1,4,5P3 functioning to release internal calcium, whereas Ins1,3,4,5P4 may function to regulate the entry of external calcium. There is evidence to suggest that these internal messengers may converge on certain key processes responsible for initiating the programme of cell growth. It is argued that an increase in intracellular calcium might be an important intracellular signal for activating both the transcription of a family of early genes, typified by fos, as well as the enzyme S6 kinase, which phosphorylates the ribosomal protein S6 which may regulate protein synthesis. The increase in pH seems to play a permissive role and may create the necessary ionic milieu for S6 phosphorylation and protein synthesis to occur. The onset of RNA and protein synthesis, which occur within the first few minutes after the arrival of a growth factor, represent the initial events of the programme of cell growth which culminates in DNA synthesis and cell division.