Send to

Choose Destination
J Biol Chem. 1996 Nov 1;271(44):27366-73.

Regulation of interleukin-2 transcription by inducible stable expression of dominant negative and dominant active mitogen-activated protein kinase kinase kinase in jurkat T cells. Evidence for the importance of Ras in a pathway that is controlled by dual receptor stimulation.

Author information

Division of Clinical Immunology and Allergy, Department of Medicine, Jonsson Cancer Center, UCLA School of Medicine, Los Angeles, California 90095, USA.


Engagement of the T cell receptor induces the activation of several mitogen-activated protein kinase modules, including the extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK) cascades. Whereas extracellular signal-regulated kinase is activated by T cell receptor/CD3 ligation alone, activation of JNK requires co-stimulation by the CD28 receptor. Activation of MEKK-1, which acts as a mitogen-activated protein kinase kinase kinase in the JNK pathway, was also induced by CD3 plus CD28 (CD3/CD28) ligation in Jurkat cells. To study the significance of the JNK cascade in T lymphocytes, we established stable Jurkat cell lines that inducibly express dominant active (DA) or dominant negative (DN) MEKK-1. Whereas expression of DA-MEKK-1 resulted in the constitutive activation of JNK along with the transcriptional activation of the minimal interleukin-2 (IL-2) promoter, DN-MEKK-1 inhibited JNK responsiveness during CD3/CD28 co-stimulation. In addition to inhibiting CD3/CD28-induced IL-2 mRNA expression, DN-MEKK-1 abrogated the transcriptional activation of the IL-2 promoter and the distal nuclear factor of activated T cells (NFAT)-activating protein 1 (AP-1) response element in that promoter. A c-Jun mutant lacking activation sites for JNK also interfered with the activation of the distal NFAT/AP-1 complex, suggesting that the JNK pathway functions by controlling AP-1 response elements in the IL-2 promoter. Using inducible stable expression of DA- and DN-Ras in Jurkat cells, we found that Ras regulates JNK activation in these cells. Our results suggest that the dual ligation of CD3 and CD28 in T cells triggers a cascade of events that involve Ras, the JNK cascade, and one or more AP-1 response elements in the IL-2 promoter.

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center