Transcriptional Regulation Notch Inhibits AP-1

The activation of Notch requires its proteolytic cleavage, which results in the translocation of the Notch intracellular domain (NICD) to the nucleus. NICD binds to the repressor protein CSL [C promoter binding factor1/RBP-J, Su(H), and Lag-1] and acts to derepress the expression of several specific genes. Chu et al. have found that, independent of its role in gene activation, NICD can inhibit the expression of activator protein-1 (AP-1)-dependent genes. Overexpression of NICD in cells transfected with AP-1 component genes greatly decreased AP-1-mediated gene expression, but had no effect on nuclear factor kappa B (NF-B)-dependent gene expression. This suggests that NICD specifically inhibited AP-1-dependent transactivation rather than affecting global gene expression. The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) in enhancing the endogenous expression of the AP-1-regulated genes interleukin-8 and matrix metalloproteinase-1 in cells treated with TPA was also inhibited by NICD. Localization of NICD to the nucleus correlated with the repression of AP-1. Additionally, NICD did not affect the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 (ERK1) or ERK2, p38, or c-Jun NH₂-terminal kinase (JNK), indicating that NICD most likely exerts its inhibitory effects in the nucleus. Thus, these data suggest that the inhibitory effects of NICD on AP-1-mediated transcription may be important for the proper regulation of cellular responses to Notch.

J. Chu, S. Jeffries, J. E. Norton, A. J. Capobianco, E. H. Bresnick, Repression of activator protein-1-mediated transcriptional activation by the Notch-1 intracellular domain. J. Biol. Chem. 277, 7587-7597 (2002). [Abstract] [Full Text]