USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

Abstract

Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.

USP5 Sustains the Proliferation of Glioblastoma Through Stabilization of CyclinD1

“…A number of USPs play critical roles in different malignant tumors via regulating cell cycle progression (Kaistha et al, 2017;Kitamura and Hashimoto, 2021;Yuan et al, 2021) and are continuously investigated as potential therapeutic targets. Recently, a variety of chemical entities were developed as USPs inhibitors, such as Pimozide, GW7674, Trifluooerazine, Rottlerin for USP1 (Chen et al, 2011), ML364, LCAHA, 6TG for USP2 (Davis et al, 2016;Magiera et al, 2017;Chuang et al, 2018), GEN-6640, GEN-6776, FT67, FT827 for USP7 (Kategaya et al, 2017;Turnbull et al, 2017).…”

Hypomorphic expression of parathyroid Bmal1 disrupts the internal parathyroid circadian clock and increases parathyroid cell proliferation in response to uremia

“…Cluster (4) constituting 12.4%, was enriched in genes for peptide biosynthesis and peaked at ZT20 (Figure1B). 6.7% of the rhythmic genes were assigned to cluster (5), with a prominent peak at ZT16, enriched by genes of cell cycle control and containing the clock genes Per1, Per2 and Cry1 as well as Usp2, which regulate cell cycle by decreasing poly-ubiquitination-dependent degradation of cyclin D1 and modulate the circadian clock by de-ubiquitination of PER1 and BMAL1 30 .…”

RNA-Seq Reveals Different Gene Expression in Liver-Specific Prohibitin 1 Knock-Out Mice

“…Besides, compared with adipose tissue from controls, toll-like receptor 2 (Tlr2) KO mice fed a high-fat diet that decreased levels of Timp1, collagen 1, and transforming growth factor-β1 (TGFβ1) (Song et al, 2018). Usp2 enhances the stability of fatty acid synthase (FASN) by impeding proteasome-dependent degradation in human HCC (Calvisi et al, 2011;Kitamura and Hashimoto, 2021). The high-fat diet-induced NAFLD rat model showed increased protein levels of SULT1E1, compared with mice-fed normal standard diet through proteomics analysis and western blots analysis (Cong et al, 2021).…”