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61.
Objective To investigate the effects of hyperglycemia on ubiquitination and endoplasmic reticulum stress in renal intrinsic cells (podocytes and proximal tubular epithelial cells) and its role in pathogenesis of diabetic nephropathy. Methods Diabetic mice were induced by streptozotocin injection. After 16 weeks of hyperglycemia, immunofluorescence was used to detect the expressions of ubiquitination and glucose-regulating protein 94 (GRP94) in renal cortex and medulla area of kidney sections. Primary mouse podocyte and proximal tubular epithelial cells were isolated by flow cytometry, and exposed to 30 mmol/L glucose for indicated time (1 d, 3 d and 7 d). Their ubiquitination and GRP94 expressions were evaluated by Western blotting. Results Diabetic mice presented microalbuminuria and slightly widened mesangium was found in glomerular area. Ubiquitinated proteins, mainly localized in podocytes and tubular epithelial cells, exhibited an apparently higher expression in diabetic mice than control mice (all P<0.05). Hyperglycemia promoted the ubiquitination in a time-dependent manner. Compared with their normal cells, primary mouse podocyte and primary tubular epithilial cells treated with high glucose for 3 d and 7 d showed increased ubiquitinated protein (all P<0.05). GRP94 was interspersed in podocytes and proximal tubular epithelial cells. Expression of GRP94 was significantly increased in glomerular area of diabetic mice and podocyte with 3 and 7 day-high glucose as compared with those in their control groups (all P<0.05). GRP94 expression had no significant change in tubular area and tubular epithilial cells treated with high glucose. Conclusions Hyperglycemia may lead to accumulation of ubiquitinated proteins in intrinsic kidney cells. The imbalance of protein homeostasis in podocyte may contribute to podocyte injury during the onset of diabetic nephropathy. 相似文献
62.
The ubiquitin-mediated proteolytic pathway as a therapeutic area 总被引:2,自引:0,他引:2
Mark Rolfe M. Isabel Chiu M. Pagano 《Journal of molecular medicine (Berlin, Germany)》1997,75(1):5-17
Ubiquitin-mediated proteolysis is involved in the turnover of many short-lived regulatory proteins. This pathway leads to
the covalent attachment of one or more multiubiquitin chains to target substrates which are then degraded by the 26S multicatalytic
proteasome complex. Multiple classes of regulatory enzymes have been identified that mediate either ubiquitin conjugation
or ubiquitin deconjugation from target substrates. Timed destruction of cellular regulators by the ubiquitin-proteasome pathway
plays a critical role in ensuring normal cellular processes. This review provides multiple examples of key growth regulatory
proteins whose levels are regulated by ubiquitin-mediated proteolysis. Pharmacological intervention which alters the half-lives
of these cellular proteins may have wide therapeutic potential. Specifically, prevention of p53 ubiquitination (and subsequent
degradation) in human papilloma virus positive tumors, and perhaps all tumors retaining wild-type p53 but lacking the retinoblastoma
gene function, should lead to programmed cell death. Specific inhibitors of p27 and cyclin B ubiquitination are predicted
to be potent antiproliferative agents. Inhibitors of IκB ubiquitination should prevent NFκB activation and may have utility
in a variety of autoimmune and inflammatory conditions. Finally, we present a case for deubiquitination enzymes as novel,
potential drug targets.
Received: 14 May 1996 / Accepted: 11 July 1996 相似文献
63.
YUSEN ZHANG LIPING LIU BIWEI LUO HONGGUI TANG XIAOFANG YU SHIYUN BAO 《Oncology research》2023,31(3):317-331
Background: Cholangiocarcinoma (CCA) represents the epithelial cell cancer with high aggressiveness whose
five-year survival rate is poor with standard treatment. Calcyclin-binding protein (CACYBP) shows aberrant expression
within several malignant tumors, but the role of CACYBP in CCA remains unknown. Methods: Immunohistochemical
(IHC) analysis was used to identify CACYBP overexpression in clinical samples of CCA patients. Moreover, its
correlation with clinical outcome was revealed. Furthermore, CACYBP’s effect on CCA cell growth and invasion was
investigated in vitro and in vivo using loss-of-function experiments. Results: CACYBP showed up-regulation in CCA,
which predicts the dismal prognostic outcome. CACYBP had an important effect on in-vitro and in-vivo cancer cell
proliferation and migration. Additionally, knockdown of CACYBP weakened protein stability by promoting
ubiquitination of MCM2. Accordingly, MCM2 up-regulation partly reversed CACYBP deficiency’s inhibition against
cancer cell viability and invasion. Thus, MCM2 might drive CCA development by Wnt/β-catenin pathway.
Conclusions: CACYBP exerted a tumor-promoting role in CCA by suppressing ubiquitination of MCM2 and
activating Wnt/β-catenin pathway, hence revealing that it may be the possible therapeutic target for CCA treatment. 相似文献
64.
The suppressor of cytokine signaling 2 (SOCS2) is a member of the SOCS family of E3 ubiquitin ligases. SOCS2 is known to regulate signal transduction by cytokine receptors and receptor tyrosine kinases. The receptor tyrosine kinase FLT3 is of importance for proliferation, survival and differentiation of hematopoietic cells and is frequently mutated in acute myeloid leukemia. We observed that SOCS2 associates with activated FLT3 through phosphotyrosine residues 589 and 919, and co-localizes with FLT3 in the cell membrane. SOCS2 increases FLT3 ubiquitination and accelerates receptor degradation in proteasomes. SOCS2 negatively regulates FLT3 signaling by blocking activation of Erk 1/2 and STAT5. Furthermore, SOCS2 expression leads to a decrease in FLT3-ITD-mediated cell proliferation and colony formation. Thus, we suggest that SOCS2 associates with activated FLT3 and negatively regulates the FLT3 signaling pathways. 相似文献
65.
From its traditional identity as a hormone involved in growth and differentiation of mammary epithelium and in lactation,
to having a pertinent role in the development of mammary carcinoma, the peptide hormone/cytokine prolactin (PRL) has emerged
as a versatile signaling molecule. There has been significant progress in our understanding of the fine working of PRL in
the past several years. Notably, much effort has been concentrated on the mediator of PRL action, namely, the prolactin receptor
(PRLr). The causal link between increased PRLr expression and breast cancer is being increasingly appreciated. Considering
that the level of the receptor on the surface is a critical determinant of signaling output in response to PRL, the uncovering
of regulatory elements that control receptor expression becomes important. The principle focus of this review is on the regulation
of PRLr expression and activity in breast cancer with a brief overview of different isoforms of PRLr, their expression, signaling
capabilities and the biological outcomes of PRL/PRLr signaling. 相似文献
66.
神经退行性疾病是一组病因不明的慢性进行性神经损害.蛋白质的错误折叠和聚集是这类疾病共同的病理特征.热休克同源蛋白70羧基端作用蛋白(carboxyl-terminus of Hsc70 interacting protein,CHIP)具有双重功能,一方面可作为热休克蛋白的辅助因子,通过氮基端的34肽重复序列结构域与Hsp90和Hsc/Hsp70相互作用,调节热休克蛋白介导的蛋白质异常折叠,同时又可作为E3泛素连接酶,通过羧基端的U-box结构域参与泛素-蛋白酶体系统(ubiqutin-proteasome system,UPS)介导的蛋白质降解过程.CHIP在分子伴侣系统和UPS的交互作用中扮演重要角色,对维持细胞内蛋白质稳态具有重要的作用.本文从CHIP蛋白的分子结构特点、生理功能、在细胞代谢中的作用、与神经退行性疾病的关系等方面进行综述. 相似文献
67.
68.
Cancer cells can survive through the upregulation of cell cycle and the escape from apoptosis induced by numerous cellular stresses. In the normal cells, these biological cascades depend on scheduled proteolytic degradation of regulatory proteins via the ubiquitin-proteasome pathway. Therefore, interruption of regulated proteolytic pathways leads to abnormal cell-proliferation. Ubiquitin ligases called SCF complex (consisting of Skp-1, cullin, and F-box protein) or CRL (cullin-RING ubiquitin ligase) are predominant in a family of E3 ubiquitin ligases that control a final step in ubiquitination of diverse substrates. To a great extent, the ubiquitin ligase activity of the SCF complex requires the conjugation of NEDD8 to cullins, i.e. scaffold proteins. This review is anticipated to review the downregulation system of NEDD8 conjugation by several factors including a chemical compound such as MLN4924 and protein molecules (e.g. COP9 signalosome, inactive mutant of Ubc12, and NUB1/NUB1L). Since the downregulation of NEDD8 conjugation affects cell-cycle progression by inhibiting the ligase activity of SCF complexes, such knowledge in the NEDD8-conjugation pathway will contribute to the more magnificent therapies that selectively suppress tumorigenesis. 相似文献
69.
70.
Ubiquitination-mediated protein modifications are increasingly recognized as key regulatory events in many basic cell biology processes. A key class of enzymes called ubiquitin ligases, which has been shown to play a crucial role in the ubiquitination process, can positively or negatively regulate T cell responses. This review summarizes the recent advances defining the roles of several ubiquitin ligases in T cell activation and autoimmunity. 相似文献