""""""""Our laboratory studies the signal transduction biology of activated T-cell and T-cell lymphoma. In the past 3 years we have identified and defined a novel gene regulatory pathway during T-cell activation through which multiple signal transduction pathways are integrated at the level of the interleukin 2 promoter. The target of this signal integration is a gene regulatory element within the interleukin 2 promoter that we have defined as the CD28RE-TRE. The CD28RE-TRE is a cis-element within the Il-2 promoter that mediates a cross-talk between the Rel/kappaB and CREB/ATF family of transcription factors. Work in the laboratory has established that this cross-talk mediates the recruitment of the p300/CBP family of transcriptional co-activators to the IL-2 promoter through specific binding sites for Rel/kappaB and CREB/ATF on p300/CBP. Moreover we have found that the coordinated action of p300, Rel/kappaB and p300 is targeted for up-regulation by T-lymphomagenic oncogenes including the Tax oncoprotein of Adult T-cell Leukemia/Lymphoma and the NPM-Alk oncogene, produced by the t(2;5) chromosomal translocation of Anaplastic Large Cell Lymphoma. Work in the laboratory has established that the mechanism of action of these important oncogenes is via their coordinated up-regulation of both CREB and Rel-dependent pathways, thus establishing CREB/Rel cross-talk as a major target for oncogene action in activated T-cell. Interestingly, we have found that the CD28RE- TRE is also a reciprocal target for tumor suppressor genes and factors that mediate apoptosis in T-cells. Work in the laboratory has demonstrated that the tumor suppressor p53 can potently transpress the CD28RE-TRE and the interleukin-2 promoter via its interaction with the C- terminal domains of p300. Notably, this repression can be nearly completely reversed by the expression of the Tax oncoprotein and the mechanism of action involves the dual ability of Tax to both directly induce transaction from the CD28RE-TRE and inhibit its trans-repression by p53. We have also found that CREB/Rel-mediated recruitment of p300 to the CD28RE-TRE is targeted for down-regulation by the glucocorticoid receptor. These findings clearly demonstrate that the interplay of p300 and CREB/Rel cross-talk at the CD28RE-TRE element is a convergent target for the action of numerous factors that control growth, mitogenesis, apoptosis and tumor suppression. Continued work in the lab is focused at identifying the molecular parameters of CREB, Rel and p300 and the upstream signaling pathways that are important for this complex interplay of molecular signaling during normal T-cell homeostasis and T-cell oncogenesis.""""""""
