The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Abstract

R e s e a R c h a R t i c l e3 4 0 7 jci.org Volume 124 Number 8 August 2014 IntroductionThe intestine is made up of repetitive units that consist of a differentiated compartment (the villus) and a proliferative compartment (the crypt). Intestinal stem cells are located in the crypt (1, 2) and produce rapidly proliferating daughter cells, the transit amplifying cells, which subsequently differentiate into 2 main epithelial lineages. The absorptive lineage is composed of all enterocytes, while the secretory lineage is composed of goblet cells (secreting protective mucins), enteroendocrine cells (secreting hormones like serotonin or secretin), and Paneth cells (3, 4). Whether transit amplifying cells differentiate along an absorptive or a secretory lineage is regulated by the Notch pathway (5). Engagement of Notch receptors by Notch ligands, such as Delta or Jagged, induces proteolytic cleavage of the receptor by γ-secretase. The cleaved NOTCH1 receptor (NICD1) translocates into the nucleus, resulting in the formation of an active transcriptional complex composed of RBPJκ (also known as CSL or CBF1) and NICD1. Notch signal activation induces hairy/enhancer of split (Hes) gene expression. Ablation of Notch signaling via genetic deletion of Rbpj results in secretory cell expansion (6). Conversely, in transgenic mice overexpressing NICD1, goblet cells are absent, and the proliferative compartment is expanded (7).The Wnt signaling pathway is a key regulator of intestinal stem cell homeostasis (8), and 2 of the target genes induced by Wnt signaling, c-MYC and c-JUN, encode transcription factors that have oncogenic potential (9, 10). Consequently, aberrant activation of the adenomatous polyposis coli/β-catenin/T cell factor (APC/ β-catenin/TCF) pathway is an initiating event in the majority of human colorectal cancers (11).c-MYC is a transcription factor with key functions in cell differentiation and cancer development (12)(13)(14). In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15-18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19-21). c-MYC ubiquitination is antagonized by the deubiquitinase USP28, which "piggybacks" on FBW7 and stabilizes c-MYC protein (22). Thus, an E3 ubiquitin ligase and a deubiquitinase, FBW7 and USP28, are together recruited to substrates (22), and a cycle of deubiquitination and ubiquitination controls c-MYC stability.Genomic data from human cancers suggest that most colorectal cancer mutations converge on c-MYC misregulation (23). Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24-29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17). Transgenic expression of a dominant-negative allele of Myc, OmoMyc, has provided proof of principle that targeting ...

Regulation of USP28 Deubiquitinating Activity by SUMO Conjugation

“…1c). The NMR structure confirms the presence of the predicted UBA domain in USP28, from Gln 22 to Lys 64 , forming a characteristic three-helix bundle domain and constituting the only globular domain in the N-terminal region of USP28 (Fig. 1).…”

“…Considerable progress has been made in the study of ubiquitin conjugation; however, the study of DUBs is still in its primary stages. Early research has been promising, implicating a number of DUBs, such as USP4 (UNP), USP6 (Tre-2), USP8 (UBPY), and USP28 and UCHL5 (UCH37) in neoplastic disease (17)(18)(19)(20)(21)(22).…”

“…However, its conditional depletion in a mouse model of colorectal cancer led to a significant increase in tumor latency, suggesting that in particular contexts, the modulation of its activity may influence cancer progression (22).…”

Once and only once: mechanisms of centriole duplication and their deregulation in disease

“…Surprisingly, USP28 knockout mice are viable and have no clear phenotypes 144,145 . Nevertheless, there is evidence to suggest that activation of the mitotic surveillance pathway could underlie the growth defects observed in primary microcephaly (see below).…”

Ubiquitin-specific protease 28 is overexpressed in human glioblastomas and contributes to glioma tumorigenicity by regulating MYC expression

“…Moreover, stabilization of MYC by USP28 is required for proliferation of several tumor cell types and inhibition of cell differentiation in colon carcinoma. 9,10 MYC is a central regulator of cell growth, proliferation, and apoptosis. Enhanced levels of MYC are thought to contribute to genesis of many human tumors, including glioma.…”