Abstract
Deubiquitinating enzymes (DUBs) are involved in the regulation of distinct critical cellular processes. Ubiquitin C-terminal Hydrolase L1 (UCH L1) has been linked to several neurological diseases as well as human cancer, but the physiological targets and the regulation of UCH L1 expression in vivo have been largely unexplored. Here we demonstrate that UCH L1 up-regulates β-catenin/TCF signaling: UCH L1 forms endogenous complexes with β-catenin, stabilizes it and up-regulates β-catenin/TCF-dependent transcription. We also show that, reciprocally, β-catenin/TCF signaling up-regulates expression of endogenous UCH L1 mRNA and protein. Moreover, using ChIP assay and direct mutagenesis we identify two TCF4-binding sites on the uch l1 promoter that are involved in this regulation. Since the expression and deubiquitinating activity of UCH L1 are required for its own basic promoter activity, we propose that UCH L1 up-regulates its expression by activation of the oncogenic β-catenin/TCF signaling in transformed cells.
Highlights
The lifetime of many central components of intracellular signaling is regulated by the ubiquitin system [1]
We immunoprecipitated with specific antibodies endogenous Ubiquitin C-terminal Hydrolase L1 (UCH L1) and b-catenin from lymphoid KR4 and epithelial 293 cells
UCH L1 and b-catenin were predominantly co-localized in the nucleus, some cytoplasmic staining for UCH L1 was observed (Fig. 1B, left)
Summary
The lifetime of many central components of intracellular signaling is regulated by the ubiquitin system [1]. The cells were cotransfected with reporter plasmids containing binding sites for TCF [29] (see Materials and Methods), along with wild type and enzymatically inactive UCH L1 mutants (expression of UCH L1 proteins was confirmed by western blot with HA antibody, Fig. 2D, top panel).
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