The role of cell cycle in the regulation of activation-induced T cell death

The orphan steroid receptor Nur77 family has been shown to be required for activation-induced death in T cell hybridoma. Activation of T cell hybridoma also results in G1 cell cycle arrest, suggesting a possible connection between the cell cycle and the apoptotic machinery. Using a yeast two-hybrid screening strategy, I identified a novel cell cycle inhibitor called p19;p19;Although the protein levels of CDK4, CDK6 and p19 are unchanged during activation-induced death of T cell hybridoma, analysis of the kinase activity of CDK2 and CDK4 shows that their activity is down while that of CDK6 is unchanged. This G1 arrest and reduced CDK activity is at least partly due to a down-regulation in the expression of cyclin D3. Interestingly, a previously unidentified 13kDa protein species associates specifically with CDK4 and CDK6 only in stimulated but not unstimulated T cell hybridoma. Thus, this novel protein may also mediate G1 arrest in T cell hybridoma.;A stable in vivo association between p19 and Nur77 is not detected in activated T cell hybridoma. However, cell cycle synchronization experiments demonstrate that DNA binding activity associated with the Nur77 family can only be detected in S phase cells, although the protein is expressed in other phases of the cell cycle. Strikingly, transactivation by Nur77 is suppressed when cyclin D are overexpressed whereas overexpression of various cell cycle inhibitors augments the transcriptional activation by Nur77. Therefore, while a stable in vivo association between p19 and Nur77 cannot be detected in T cell hybridoma, the activity of Nur77 is nevertheless modulated by the cell cycle machinery. Thus, the cell cycle may play a role in activation-induced T cell death by regulating the activity of Nur77.