We study the effect of low oxygen (hypoxia) on cell cycle regulation, apoptosis, cellular metabolism, and development. Many tumors are severely hypoxic, and hypoxic tumors have a poorer prognosis than non-hypoxic tumors. While most normal cells growth arrest when hypoxic, we have demonstrated that some neoplastic cells, as well as cells we have manipulated with oncogenes, can proliferate even when hypoxic. Using biochemistry, molecular biology, and cell biology techniques we have delineated two specific cell cycle checkpoints that are activated in hypoxic cells: an Rb mediated G1 arrest, and an S phase arrest that is due to the suppression of the initiation step of DNA replication. We are determining how the DNA initiation complex is altered in hypoxic cells, and the role of the ATR kinase (which we have observed is activated in hypoxic cells) in this alteration. We have also determined that the helix-loop-helix inhibitor, Id-1, is transcriptionally down-regulated in hypoxic cells. This down-regulation is dependent on activation of the activation of the unfolded-protein response, and we and are exploring the mechanism and significance of this observation.