Destroyed by Notch

Abstract

Signaling by the Notch receptor is one important pathway that inhibits differentiation in order to maintain a pool of multipotent precursor cells. Activation of the Notch receptor results in cleavage of the Notch intracellular domain, which has well-characterized functions as a transcriptional regulator. Sriuranpong et al. studied small cell lung carcinoma cell lines overexpressing various components of the Notch signaling pathway to elucidate a posttranslational regulatory mechanism in addition to Notch's transcriptional regulatory pathway. Overexpression of an active Notch intracellular domain (ICD) inhibited the expression of human acheate-scute homolog1 (hASH1) through a mechanism dependent on the Hairy-enhancer of Split transcriptional repressor (HES1). In addition, the overexpressed Notch ICD decreased the half-life of hASH and increased the turnover of hASH1 through a ubiquitin-dependent and proteasome-dependent degradation process. hASH1 is transcriptional regulator that dimerizes with another basic helix-loop-helix protein to transactivate genes with E box-containing promoters. Coexpression of the hASH1 partner E12 enhanced hASH1 stability and protected hASH1 from increased degradation stimulated by the overexpressed Notch ICD. Thus, Notch may act through two pathways: (i) as a transcription factor to regulate gene expression at the level of transcription and (ii) as a stimulator of protein turnover through a mechanism involving the proteasome-mediated destruction of Notch-targeted substrates.V. Sriuranpong, M. W. Borges, C. L. Strock, E. K. Nakakura, D. N. Watkins, C. M. Blaumueller, B. D. Nelkin, D. W. Ball, Notch signaling induces rapid degradation of achaete-scute homolog 1. Mol. Cell. Biol. 22, 3129-3139 (2002). [Abstract] [Full Text]