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Inositol lipids and DNA replication
1Department of Zoology, University of Cambridge, U.K.
Abstract:
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.
Insights
Growth factors trigger DNA synthesis via intracellular signals like calcium and pH changes. These signals activate early genes and protein synthesis, initiating cell growth and division.
Area of Science:
- Cellular Biology
- Molecular Signaling
Background:
- Growth factors control DNA synthesis through intracellular mitogenic signals.
- Tyrosine kinase activity and changes in calcium and hydrogen ion concentrations are key events.
- Hydrolysis of inositol lipids generates important second messengers.
Purpose of the Study:
- To elucidate the role of intracellular signals in growth factor-mediated DNA synthesis.
- To identify key second messengers and their downstream effects.
- To understand the convergence of these signals on cell growth initiation.
Main Methods:
- Investigated the role of tyrosine phosphorylation in signal transduction.
- Analyzed changes in intracellular calcium and pH.
- Examined the metabolism and function of inositol phosphates, including inositol 1,4,5-trisphosphate (Ins1,4,5P3) and inositol 1,3,4,5-tetrakisphosphate (Ins1,3,4,5P4).
Main Results:
- Growth factors stimulate inositol lipid hydrolysis, producing diacylglycerol and Ins1,4,5P3.
- Ins1,4,5P3 releases intracellular calcium, while Ins1,3,4,5P4 may regulate calcium entry.
- Increased intracellular calcium and pH activate early gene transcription (e.g., fos) and S6 kinase, promoting protein synthesis.
Conclusions:
- Intracellular calcium and pH are critical signals initiating cell growth.
- These signals converge to regulate early gene expression and protein synthesis, preceding DNA synthesis.
- Understanding these pathways is crucial for comprehending cell division control.