The concerted action of CDK2 inhibition and increased pRB dephosphorylation leads to the net accumulation of pRB in its active, hypophosphorylated form. This results in G 1 growth arrest through repression of early S phase gene transcription and consequent inhibition of DNA synthesis. In addition, DNA synthesis may also be directly affected through inhibition of cyclin A-associated kinase activity. Long term hypoxia results in a decrease in both cyclin A and cyclin E abundance. Consequently, there are fewer active cyclin-CDK2 complexes available and lower concentrations of p27 are needed for their inhibition, which may account for the lower levels of p27 observed.
Question marks designate hypothetical pathways.
As presented, there is a sense of these enzymes working together to ensure that, when proliferation conditions are not optimal, a key regulator of cell cycle progression is activated to stop proliferation by maintaining it in a hypophosphorylated form. Additionally, this hypoxia system may be more extensively used to study the synergy between kinase and phosphatase activity with regard to other biochemical aspects of cell cycle regulation.