Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin-specific protease 2 (USP2) is a member of a family of de-ubiquitinating enzymes. It may play an important role in the regulation of cell growth and differentiation. It is known that expression of the isoform USP2-69 kD is high in kidney tissue, but its role remains unclear. Mesangial cell proliferation is a prominent element of various types of glomerulonephritides. Therefore, whether USP2 plays a role in mesangial cell proliferation during glomerulonephritides is an interesting question to explore. The purpose of the present study was to evaluate USP2-69 expression in needle biopsies of human kidneys and in cultured rat mesangial cells. On immunohistochemistry USP2-69 was upregulated in some mesangial proliferative glomerulonephritides. The proportion of USP2-69 positive area in the glomeruli was 3.90% in normal kidney, 4.96% in minimal change disease, and 4.39% in membranous glomerulonephritides, while it was 14.84% in IgA nephropathy (IgAN) (mesangial proliferative type), 16.18% in lupus nephritis (LN; diffuse proliferative type) and 15.54% in acute proliferative glomerulonephritides (APGN); the difference of the percentages between IgAN, LN (IV subtype) and APGN and normal kidney were statistically significant (P < 0.05). Additionally, the number of proliferating cell nuclear antigen (PCNA)-positive nuclei in the glomeruli was statistically significantly higher in the various glomerulonephritides than in the normal kidney (P < 0.05). Immunohistochemistry showed that the distribution of the USP2(+) area and PCNA(+) nuclei overlapped in the glomeruli. Treatment with interleukin-1beta for 12 h and 24 h, or with anti-thymocyte serum for 6 h and 12 h resulted in elevated USP2-69 mRNA and protein expression in the rat mesangial cells. Also, PCNA expression increased and p27 expression decreased significantly in the treated mesangial cells. These findings suggest that USP2-69 was upregulated in mesangial cells during mesangial proliferative glomerulonephritides in vivo and in vitro, which may relate to the proliferation of mesangial cells.
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PMID:Expression of USP2-69 in mesangial cells in vivo and in vitro. 2040 44

Ubiquitin conjugation (ubiquitylation) plays important roles not only in protein degradation but also in many other cellular functions. However, the sites of proteins that are targeted for such modification have remained poorly characterized at the proteomic level. We have now developed a method for the efficient identification of ubiquitylation sites in target proteins with the use of an engineered form of ubiquitin (K0-Ub), in which all seven lysine residues are replaced with arginine. K0-Ub is covalently attached to lysine residues of target proteins via an isopeptide bond, but further formation of a polyubiquitin chain does not occur on K0-Ub. We identified a total of 1392 ubiquitylation sites of 794 proteins from HEK293T cells. Profiling of ubiquitylation sites indicated that the sequences surrounding lysine residues targeted for ubiquitin conjugation do not share a common motif or structural feature. Furthermore, we identified a critical ubiquitylation site of the cyclin-dependent kinase inhibitor p27(Kip1). Mutation of this site thus inhibited ubiquitylation of and stabilized p27(Kip1), suggesting that this lysine residue is the target site of p27(Kip1) for ubiquitin conjugation in vivo. In conclusion, our method based on K0-Ub is a powerful tool for proteome-wide identification of ubiquitylation sites of target proteins.
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PMID:Proteome-wide identification of ubiquitylation sites by conjugation of engineered lysine-less ubiquitin. 2205 31

Ubiquitin-proteasome system (UPS) plays a crucial role in many cellular processes such as cell cycle, proliferation and apoptosis. Aberrant activation of UPS may result in cellular transformation or other altered pathological conditions. Previous studies have shown that metal-based complexes could inhibit proteasome activity and induce apoptosis in certain human cancer cells. In the current study, we report that the cadmium and copper complexes with heterocycle-ornithine Schiff base are potent inhibitors of proteasomal chymotrypsin-like (CT-like) activity, leading to induction of apoptosis in cancer cells. Two novel copper-containing complexes and two novel cadmium-containing complexes with different heterocycle-ornithine Schiff base structures as ligands were synthesized and characterized. We found that complexes Cu1, Cd1 and Cd2 show proteasome-inhibitory activities in human breast cancer MDA-MB-231 and human prostate cancer LNCaP cells, resulting in the accumulation of p27, a natural proteasome substrate and other ubiquitinated proteins, followed by the induction of apoptosis. Our results suggest that metal complexes with heterocycle-ornithine Schiff base have proteasome-inhibitory capabilities and have the potential to be developed into novel anticancer drugs.
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PMID:L-Ornithine Schiff base-copper and -cadmium complexes as new proteasome inhibitors and apoptosis inducers in human cancer cells. 2546 55

The human genome contains six genes coding for proteins validated in vitro as specific activators of the small GTPases "Ras-related protein Ral-A" and "Ras-related protein Ral-B", generically named Ral-guanine nucleotide exchange factors (RalGEF). Ral proteins are important contributors to Ras oncogenic signaling, and RAS oncogenes are important in human Non-Small Cell Lung Carcinoma (NSCLC). Therefore in this work, RalGEF contribution to oncogenic and non-oncogenic features of human NSCLC cell lines, as anchorage-dependent and independent growth, cell survival, and proliferation, was investigated. Among all human RalGEF, silencing of RGL1 and RALGPS1 had no detectable effect. However, silencing of either RGL2, RGL3, RALGDS or, to a larger extent, RALGPS2 inhibited cell population growth in anchorage dependent and independent conditions (up to 90 and 80%, respectively). RALGPS2 silencing also caused an increase in the number of apoptotic cells, up to 45% of the cell population in transformed bronchial BZR cells. In H1299 and A549, two NSCLC cell lines, RALGPS2 silencing caused an arrest of cells in the G0/G1-phase of cell cycle. Furthermore, it was associated with the modulation of important cell cycle regulators: the E3 Ubiquitin Protein Ligase S-phase kinase-associated protein 2 (Skp2) was strongly down-regulated (both at mRNA and protein levels), and its targets, the cell cycle inhibitors p27 and p21, were up-regulated. These molecular effects were not mimicked by silencing RALA, RALB, or both. However, RALB silencing caused a modest inhibition of cell cycle progression, which in H1299 cells was associated with Cyclin D1 regulation. In conclusion, RALGPS2 is implicated in the control of cell cycle progression and survival in the in vitro growth of NSCLC cell lines. This function is largely independent of Ral GTPases and associated with modulation of Skp2, p27 and p21 cell cycle regulators.
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PMID:RalGPS2 Is Essential for Survival and Cell Cycle Progression of Lung Cancer Cells Independently of Its Established Substrates Ral GTPases. 2714 77

Ubiquitinylation drives many cellular processes by targeting proteins for proteasomal degradation. Ubiquitin conjugation enzymes promote ubiquitinylation and, thus, degradation of protein substrates. Ubiquitinylation is a well-known posttranslational modification controlling cell-cycle transitions and levels or/and activation levels of ubiquitin-conjugating enzymes change during development and cell cycle. Progression through the cell cycle is tightly controlled by CDK inhibitors such as p27Kip1. Here we show that, in contrast to promoting its degradation, the ubiquitin-conjugating enzyme UBCH7/UBE2L3 specifically protects p27Kip1 from degradation. Overexpression of UBCH7/UBE2L3 stabilizes p27Kip1 and delays the G1-to-S transition, while depletion of UBCH7/UBE2L3 increases turnover of p27Kip1. Levels of p21Cip1/Waf1, p57Kip2, cyclin A and cyclin E, all of which are also involved in regulating the G1/S transition are not affected by UBCH7/UBE2L3 depletion. The effect of UBCH7/UBE2L3 on p27Kip1 is not due to alteration of the levels of any of the ubiquitin ligases known to ubiquitinylate p27Kip1. Rather, UBCH7/UBE2L3 catalyzes the conjugation of heterotypic ubiquitin chains on p27Kip1 that are proteolytically incompetent. These data reveal new controls and concepts about the ubiquitin proteasome system in which a ubiquitin-conjugating enzyme selectively inhibits and may even protect, rather than promote degradation of a crucial cell-cycle regulatory molecule.-Whitcomb, E. A., Tsai, Y. C., Basappa, J., Liu, K., Le Feuvre, A. K., Weissman, A. M., Taylor, A. Stabilization of p27Kip1/CDKN1B by UBCH7/UBE2L3 catalyzed ubiquitinylation: a new paradigm in cell-cycle control.
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PMID:Stabilization of p27Kip1/CDKN1B by UBCH7/UBE2L3 catalyzed ubiquitinylation: a new paradigm in cell-cycle control. 3011 82

MicroRNA-216b (miR-216b) has been reported to be downregulated in several tumors, its mechanism is still little-studied in hepatocellular carcinoma (HCC). In the present study, we found that miR-216b was downregulated in HCC, but Ubiquitin-specific peptidase 28 (USP28) was upregulated. In addition, Kaplan-Meier-plotter analysis indicated that liver cancer patients with high miR-216b expression had a longer overall survival, but patients with high USP28 had a shorter overall survival. Further studies showed that overexpression of miR-216b inhibited HCC cell growth, and molecular investigations revealed that miR-216b targeted USP28 and inhibited its expression in HCC cells. In addition, overexpression of miR-216b suppressed the substrates' expression of USP28, for example, c-Myc, and miR-216b overexpression also inhibited Cyclin E expression as well as upregulating p27 expression, both of which were the downstream signals of c-Myc. These results indicated that miR-216b downregulated USP28/c-Myc signaling in HCC cells. Collectively, this study demonstrated that miR-216b/c-Myc axis could be as a potential target for HCC therapy in the future.
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PMID:MicroRNA-216b suppresses the cell growth of hepatocellular carcinoma by inhibiting Ubiquitin-specific peptidase 28 expression. 3205 84


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