Usp28 counteracts Fbw7 in intestinal homeostasis and cancer.

ABSTRACT: The stability of several oncoproteins, including c-Myc, is regulated by ubiquitin-dependent degradation mediated by the SCF(Fbw7) ubiquitin ligase. This activity is antagonized by the deubiquitinase Usp28, which is highly expressed in murine and human intestinal cancers. Usp28 was previously shown to interact with its substrates via a "piggyback" interaction with Fbw7, which suggested that Fbw7 is required for Usp28 activity. Unexpectedly, we found that genetic deletion of Usp28 rescued the lethality of Fbw7-deficient primary fibroblasts. Moreover, Usp28 inactivation in the intestine (Usp28(ΔIEC)) ameliorated the hyperproliferation and the impaired goblet and Paneth cell differentiation observed in Fbw7(ΔIEC) mice. The aggressive intestinal tumor formation of APC(Min/+); Fbw7(ΔIEC) mice wa

SUBMITTER: Diefenbacher ME 

PROVIDER: S-EPMC4384988 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature