Regulation of the Cell Cycle
• The cell has four choices
• Cell cycle phases include G1, S, G2 and M
• Checkpoints exist throughout the cell cycle
• Restriction point (Rb) in G1 phase blocks cells from committing to
the proliferative cycle unless nutrients and mitogens are present
and the cell senses appropriate interaction with the extracellular
matrix. This must be passed in order to proliferate.
• DNA damage checkpoints in G1, S and G2 phases that are con-
trolled by p53
• Metaphase-anaphase checkpoint (spindle assembly checkpoint)
• Under certain conditions, including high cell density and an absence of
growth factors, mammalian cells will accumulate in 2n DNA content.
Most researchers now agree that this represents not just a very slow G1
phase but a distinct phase outside the normal cell cycle
• G0 - Non-proliferative state that may last hours or days. Do not express
cyclins and have low CDK activity.
• Acute down-regulation of pRb causes cells to exit quiescence and
re-enter the cell cycle
• Phosphorylation status of pRb is controlled by cyclins and cyclin-
dependent kinases (CDKs)
• Levels of cyclin D increase in response to the presence of extra-
• Cells that are in quiescence must re-enter the cell cycle by pass-
ing the G0 checkpoint and entering G1
• Extracellular mitogens excite receptors the cell surface,
which then activate Ras and MAPKs, which then activate
transcription factors that induce the production of c-fos and
c-jun. C-fos and c-jun induce the transcription of cyclin D.
• In the absence of growth factors and cytokines, cyclin D is
• If cyclin D is allowed to accumulate, it causes the phospho-
rylation of Rb by activating Cdk4/6. Once Rb is phosphory-