Evidence for the Involvement of Tyrosine Kinase ZAP 70 in Nuclear Retinoid Receptor-dependent Transactivation in T Lymphocytes

Ishaq M, Degray G and Natarajan V
Source: J Biol Chem
Publication Date: (2005)
Issue: 280(40): 34152-34158
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are transcription factors that control diverse cellular functions during development and homeostasis. The biochemical role of these proteins in T lymphocytes is not well known. Here we have studied the role of protein-tyrosine kinase ZAP 70, a key enzyme involved in the proximal signaling events during T cell activation, in the modulation of RXRE- and RARE-dependent activation in T lymphocytes. Surprisingly, ZAP 70-negative Jurkat T cells showed considerable loss of both RXRE- and RARE-mediated transactivation as compared with wild type Jurkat cells. In addition, ZAP 70-negative cells failed to exhibit normal protein kinase C and calcineurin-induced transcriptional activity. ZAP 70-negative cells that were reconstituted with active ZAP 70 regained the transactivation function, whereas cells expressing kinase-dead form of ZAP 70 failed to do so. Defective transcriptional activation was also observed in actively proliferating human peripheral blood T lymphocytes in which RNA interference was used to induce loss of ZAP 70 expression. In addition, an Lck-deficient Jurkat cell line that cannot efficiently activate ZAP 70 was also found defective in RXRE-mediated transcription. Finally, RNA interference-induced loss of ZAP 70 or Lck protein in Jurkat cells resulted in significant decrease in the RXRE-dependent activation. Together, these results suggest a novel functional role for ZAP 70 in nuclear receptor-driven transactivation in T lymphocytes.