Identification of a novel inhibitor of mitogen-activated protein kinase kinase.

The compound U0126 (1,4-diamino-2,3-dicyano-1, 4-bis[2-aminophenylthio]butadiene) was identified as an inhibitor of AP-1 transactivation in a cell-based reporter assay. U0126 was also shown to inhibit endogenous promoters containing AP-1 response elements but did not affect genes lacking an AP-1 response element in their promoters. These effects of U0126 result from direct inhibition of the mitogen-activated protein kinase kinase family members, MEK-1 and MEK-2.

The p38 mitogen-activated protein kinase pathway in activated and anergic Th1 cells.

Stimulation of T cells through the TCR leads to activation of the mitogen-activated protein kinase (MAPK) family members ERK (extracellular signal-regulated kinase) and JNK (jun NH2-terminal kinase). These kinases act in synergy to increase the activity of the transcription factor AP-1 which is involved in the transcriptional upregulation of IL-2. Recently a third MAPK member, p38, has been identified.

The effects of IL-1 on mitogen-activated protein kinases in rabbit articular chondrocytes.

IL-1-activated chondrocytes express a large number of genes which contribute to cartilage degradation. The signaling pathways activated in response to IL-1 in these cells are not well-defined. We examined the effects of IL-1 and other stimuli on the mitogen activated protein kinase (MAPK) pathways in rabbit articular chondrocytes.

Anergic T cells are defective in both jun NH2-terminal kinase and mitogen-activated protein kinase signaling pathways.

T helper type 1 cells (Th1) become anergic when stimulated through the antigen receptor in the absence of costimulation. They do not produce IL-2 or proliferate in response to subsequent stimulation. Previous studies have indicated that anergic T cells are defective in the trnsactivational activity of the transcription factor, AP-1, which is required for optimal IL-2 transcription.

Multiple sites of the propeptide region of human stromelysin-1 are required for maintaining a latent form of the enzyme.

Latency of matrix metalloproteinase 3 (MMP-3) is regulated by the interaction of a free cysteine residue (Cys-75) in the conserved amino acid sequence Pro-Arg-Cys-Gly-Val-Pro-Asp located in the COOH-terminal portion of the propeptide with a chelated zinc atom in the active site of the catalytic domain. Proteolytic activation of full-length human pro-MMP-3 involves the removal of approximately 35 amino acids from the NH2-terminal portion of the propeptide, forming a 53-kDa unstable intermediate that undergoes intermolecular autocatalysis to form the 45-kDa mature active enzyme. In this study, we have evaluated the contribution of the NH2-terminal 35 amino acids to the maintenance of latency.