Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Role of tumor suppressor phosphoprotein p53 in signal transduction during lymphocyte activation: implications for viral pathogenesis.
Diss Abstr Int [B]; 55(3):811 1994. Unique Identifier : AIDSLINE ICDB/95607551 McClure JE; Baylor College of Medicine
Abstract:
Employing the competition RIA for studies of the levels of Domain V in sub-cellular compartments during acute stimulations of CHX-treated lymphocytes, we observed rapidly (10-20 min) increased levels of cytosolic IRp53 and decreased levels of nuclear IRp53. We determined that a 3- to 4-fold increase of readily-extractable IRp53 occurred in T cells activated with ConA/serum indicating that a mobilization or release from a masked state had taken place. Treatment in vitro of purified T cell p53 and recombinant p53 from sf9 cells with alkaline phosphatase revealed that IRp53 increased with dephosphorylation of p53. Additional treatments of p53 with purified cellular enzymes identified phosphatase PP2A as capable of dephosphorylating p53 and increasing IRp53 while the kinase casein kinase II was capable of phosphorylating p53 and decreasing IRp53. Treatments of cells with okadaic acid (1 nM) while they were being activated revealed that OA totally inhibited increases of cytosolic IRp53 while kinase inhibitor staurosporine (100 nM) inhibited the decline of nuclear IRp53 levels that was associated with phosphorylation of nuclear p53. Thus Domain V was determined to be a C-terminal domain that was unmasked through dephosphorylation and masked through phosphorylation. We demonstrated that PAB421 binding of p53 increased IRp53 and therefore it is likely that protein binding to p53 and/or changes in its oligomerization contribute to unmasking of Domain V and probably to its subcellular re-localization during cell activation. Ligation of B or T lymphocytes by various activating ligands produced the p53 translocation event. Engagement of the TCR, an event known to generate a signal for apoptosis in immature thymocytes, resulted in a rise of intracellular Ca++ and p53 translocation. Activation of resting B cells with phorbol ester produced dose-dependent cell proliferation and p53 translocation, and proliferation correlated with the amplitude of the p53 event. Ligation of cellular receptors by virus components or virions (CD4 by gp120/anti-gp120, or CD21 by EBV) was accompanied by p53 translocation. We propose that the p53 pathway may operate in parallel with cell activating signal pathways in order to modulate the proliferative response of cells to growth signals. Lymphocytotropic viruses activate resting host cells to proliferation in order to promote efficient virus production, and p53 translocation may be a normal event in cell activation by virus. On the other hand, DNA tumor viruses encode oncoproteins that bind p53, perhaps hinder its normal dephosphorylation and conformational change, and thereby contribute to cellular growth transformation. (Abstract shortened by UMI.) (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-18963)
Keywords: B-Lymphocytes/METABOLISM Biological Transport Herpesvirus 4, Human/*METABOLISM HIV Envelope Protein gp120/METABOLISM HIV-1/METABOLISM *Lymphocyte Transformation Phosphorylation Protein p53/*METABOLISM Receptors, Complement 3d/METABOLISM *Signal Transduction T-Lymphocytes/METABOLISM THESIS 950830
M9581001
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
