| T-cell activation is a critical event in an antigen specific immune response and is marked by induced T-cell growth factor (Interleukin-2 , IL-2) gene expression and the associated T-cell proliferation. Transcription is the primary mode for IL-2 level regulation and has been previously demonstrated to be dependent on a ubiquitous nuclear transcriptional coactivator protein, termed p300. Interaction between the tumor suppressor protein, p53, and p300 are widely recognized as important in controlling gene expression at various promoters. This work defines a molecular interplay between p53 and p300 that results in transcriptional repression of IL-2 gene expression. The Tax oncoprotein, a product of the Human T-cell Lymphotrophic Virus-1 (HTLV-1), targets the proximal IL-2 promoter and reverses this p53 mediated transcriptional repression. Interestingly, the endogenous p53 inhibitor, murine double minute-2 (mdm-2) is not able to antagonize the p53-mediated repression. Instead, it acts synergistically with p53 to induce repression. Mdm-2 over-expression alone results in similar repression of the IL-2 promoter activity as well as a reduction in the transcriptional potential of p300. This mdm-2 mediated repression is not reversible by Tax. Targeting of the IL-2 gene is surprisingly selective since the interaction between p53 and Tax synergistically trans-activates, rather than represses, the promoter of the cyclin dependent kinase inhibitor p21.; In biological assays using lymphoid cells, p53 and Tax employ mutually exclusive pathways to induce apoptosis. Interestingly, both the pathways are antagonistic in activated T-cells. In each case, mdm-2 coexpression was protective. This anti-apoptotic action of mdm-2 in lymphoid cells is linked to the ability of mdm-2 to antagonize the expression of Fas-Ligand ( FasL) in activated T-cells.; This data provides evidence for a role for p53 in limiting activated T-cell proliferation by repressing IL-2 gene expression and/or inducing apoptosis; furthermore, mdm-2 may serve to uncouple p53 mediated transcriptional repression and apoptosis induction. The Tax-p53 interplay described herein may be a major control point for the promotion of viral proliferation and cellular transformation. Since the steady state levels of mdm-2 may be a key regulator of Tax dependent transformation in HTLV-1 infected cells, aberrant mdm-2 expression may be a useful marker in identifying individuals susceptible to T-cell transformation. Evidence provided in this work demonstrate that dysregulation of factors like p53, mdm-2 and p300 can have a major role in the development of lymphoid neoplasia, autoimmune disease and immunodeficiency. |
