From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization
TL;DR: In this paper, the authors highlight old observations and recent advances in the knowledge regarding protein stabilization in cancer and suggest that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer.
Abstract: A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by the substrate-recognition enzyme, E3 ubiquitin ligase. Stabilization may also result from the inactivation of the enzymatic machinery that mediates the degradation of oncoproteins. Importantly, inactivation in cancer of E3 enzymes that regulates the physiological degradation of oncoproteins, results in tumor cells that accumulate multiple active oncoproteins with prolonged half-lives, leading to the development of “degradation-resistant” cancer cells. In addition, specific sequences may enable ubiquitinated proteins to evade degradation at the 26S proteasome. While the ubiquitin-proteasome pathway was originally discovered as central for protein degradation, in cancer cells a ubiquitin-dependent protein stabilization pathway actively translates transient mitogenic signals into long-lasting protein stabilization and enhances the activity of key oncoproteins. A central enzyme in this pathway is the ubiquitin ligase RNF4. An intimate link connects protein stabilization with tumorigenesis in experimental models as well as in the clinic, suggesting that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer. In this review, we highlight old observations and recent advances in our knowledge regarding protein stabilization.
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TL;DR: Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that is constitutively expressed in the nucleus of epithelial, endothelial and fibroblast-like cells as discussed by the authors .
9 citations
Journal Article•
01 Jan 2022TL;DR: In this article , the authors reviewed recent research advances in HCC-associated E3 ligases, described their structure, classification, functional roles, and discussed some mechanisms of abnormal activation or inactivation of the HCCassociated signal pathway due to the binding of E3 to known substrates.
Abstract: Hepatocarcinogenesis is a complex multistep biological process involving genetic and epigenetic alterations that are accompanied by activation of oncoproteins and inactivation of tumor suppressors, which in turn results in Hepatocellular carcinoma (HCC), one of the common tumors with high morbidity and mortality worldwide. The ubiquitin-proteasome system (UPS) is the key to protein degradation and regulation of physiological and pathological processes, and E3 ligases are key enzymes in the UPS that contain a variety of subfamily proteins involved in the regulation of some common signal pathways in HCC. There is growing evidence that many structural or functional dysfunctions of E3 are engaged in the development and progression of HCC. Herein, we review recent research advances in HCC-associated E3 ligases, describe their structure, classification, functional roles, and discuss some mechanisms of the abnormal activation or inactivation of the HCC-associated signal pathway due to the binding of E3 to known substrates. In addition, given the success of proteasome inhibitors in the treatment of malignant cancers, we characterize the current knowledge and future prospects for targeted therapies against aberrant E3 in HCC.
4 citations
TL;DR: The drivers and functions of phase separation are summarized, the roles ofphase separation in tumor pathogenesis and evolution are elaborate, and substantial research and therapeutic prospects for phase separation in cancer are proposed.
3 citations
TL;DR: A novel regulatory effect of the UBE2B/RAD18 complex on ZMYM2 monoubiquitination and stability in ovarian cancer is revealed.
Abstract: ABSTRACT Ubiquitin-conjugating enzyme E2 B (UBE2B) can form a heterodimer with ubiquitin E3 ligase RAD18. In this study, we aimed to explore new substrates of the UBE2B/RAD18 complex and their regulatory effects in ovarian cancer. Protein physical interactions were predicted using GeneMANIA. Serial sections of commercial ovarian cancer tissue arrays were used to check the protein expression of UBE2B, RAD18, and ZMYM2. Immunofluorescence staining and co-immunoprecipitation assays were performed to check their location and interactions. Cycloheximide chase assay was applied to explore the influence of UBE2B and RAD18 on ZMYM2 degradation. Xenograft tumor models were constructed to assess the influence of the UBE2B-ZMYM2 axis on in vivo tumor growth. A strong positive correlation between UBE2B and ZMYM2 and a moderate positive correlation between RAD18 and ZMYM2 were observed in 23 ovarian cancer cases. In CAOV4 and OVCAR3 cells, myc-ZMYM2 interacted with UBE2B and RAD18. UBE2B and ZMYM2 could be detected in the samples immunoprecipitated by anti-RAD18. UBE2B overexpression or knockdown did not alter ZMYM2 mRNA expression. UBE2B overexpression increased ZMYM2 monoubiquitination but reduced its polyubiquitination. RAD18 knockdown impaired UBE2B-induced ZMYM2 monoubiquitination. UBE2B overexpression significantly enhanced the stability of ZMYM2 protein, the effect of which was weakened by RAD18 knockdown. UBE2B overexpression significantly enhanced the growth of xenograft tumors derived from CAOV4 cells. ZMYM2 knockdown remarkedly suppressed tumor growth and impaired the growth-promoting effect of UBE2B overexpression. In conclusion, this study revealed a novel regulatory effect of the UBE2B/RAD18 complex on ZMYM2 monoubiquitination and stability in ovarian cancer. Graphic Abstract
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TL;DR: In this article , the RNF4 ubiquitin ligase is essential for osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs).
Abstract: Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSCs remain as stalled progenitors. Remarkably, incubation of RNF4-deficient hBMSCs in conditioned media of differentiating hBMSCs restored OD. Transcriptional analysis of RNF4-dependent gene signatures identified two secreted factors that act downstream of RNF4 promoting OD: (1) BMP6 and (2) the BMP6 co-receptor, RGMb (Dragon). Indeed, knockdown of either RGMb or BMP6 in hBMSCs halted OD, while only the combined co-addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restored OD. Moreover, we found that the RNF4-RGMb-BMP6 axis is essential for survival and tumorigenicity of osteosarcoma and therapy-resistant melanoma cells. Importantly, patient-derived sarcomas such as osteosarcoma, Ewing sarcoma, liposarcomas, and leiomyosarcomas exhibit high levels of RNF4 and BMP6, which are associated with reduced patient survival. Overall, we discovered that the RNF4~BMP6~RGMb axis is required for both OD and tumorigenesis.
3 citations
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TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Abstract: The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.
7,888 citations
TL;DR: Recent progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1.
Abstract: NF-κB (nuclear factor-κB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-κ...
4,724 citations
TL;DR: The c-MYC oncogene is identified as a target gene in this signaling pathway and shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c- MYC promoter.
Abstract: The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
4,686 citations
TL;DR: It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
Abstract: The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
4,311 citations
TL;DR: Results indicate that regulation of β-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β- catenin.
Abstract: Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by beta-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta-catenin.
3,859 citations