Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging regulator of cell growth and apoptosis in various cell types, tissues and organisms. Previous work indicates that HIPK2 is a potential tumour suppressor and DNA damage-responsive kinase, which phosphorylation-dependently activates the apoptotic programme by engaging diverse downstream targets, including tumour suppressor p53 and the anti-apoptotic transcriptional corepressor C-terminal binding protein. The regulation of HIPK2, however, remained largely obscure. Recent studies show that HIPK2 activity is mainly controlled at the post-transcriptional level through targeted proteolysis. Caspase-dependent processing triggers HIPK2 hyperactivation, whereas the ubiquitin-proteasome system (UPS) keeps HIPK2 in check by targeting it for degradation. Both HIPK2 hyperactivation and HIPK2 degradation are under the control of transcription factor p53. Negative regulation of HIPK2 by the UPS is abolished in response to DNA damage, which facilitates HIPK2 stabilization and activation. Here we discuss these findings in the context of DNA damage signalling and tumour suppression.
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PMID:How cells switch HIPK2 on and off. 1897 74

The objective was to identify proteins differentially expressed in vaginal cancer to elucidate relevant cancer-related proteins. A total of 16 fresh-frozen tissue biopsies, consisting of 5 biopsies from normal vaginal epithelium, 6 from primary vaginal carcinomas and 5 from primary cervical carcinomas, were analysed using two-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry. Of the 43 proteins identified with significant alterations in protein expression between non-tumourous and tumourous tissue, 26 were upregulated and 17 were downregulated. Some were similarly altered in vaginal and cervical carcinoma, including cytoskeletal proteins, tumour suppressor proteins, oncoproteins implicated in apoptosis and proteins in the ubiquitin-proteasome pathway. Three proteins were uniquely altered in vaginal carcinoma (DDX48, erbB3-binding protein and biliverdin reductase) and five in cervical carcinoma (peroxiredoxin 2, annexin A2, sarcomeric tropomyosin kappa, human ribonuclease inhibitor and prolyl-4-hydrolase beta). The identified proteins imply involvement of multiple different cellular pathways in the carcinogenesis of vaginal carcinoma. Similar protein alterations were found between vaginal and cervical carcinoma suggesting common tumourigenesis. However, the expression level of some of these proteins markedly differs among the three tissue specimens indicating that they might be useful molecular markers.
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PMID:Differential tissue-specific protein markers of vaginal carcinoma. 1936 86

In response to DNA damage, eukaryotic cells initiate a complex signalling pathway, termed the DNA damage response (DDR), which coordinates cell cycle arrest with DNA repair. Studies have shown that oncogene-induced senescence, which provides a barrier to tumour development, involves activation of the DDR. Using a genome-wide RNA interference (RNAi) screen, we have identified 17 factors required for oncogenic BRAF to induce senescence in primary fibroblasts and melanocytes. One of these factors is an F-box protein, FBXO31, a candidate tumour suppressor encoded in 16q24.3, a region in which there is loss of heterozygosity in breast, ovarian, hepatocellular and prostate cancers. Here we study the cellular role of FBXO31, identify its target substrate and determine the basis for its growth inhibitory activity. We show that ectopic expression of FBXO31 acts through a proteasome-directed pathway to mediate the degradation of cyclin D1, an important regulator of progression from G1 to S phase, resulting in arrest in G1. Cyclin D1 degradation results from a direct interaction with FBXO31 and is dependent on the F-box motif of FBXO31 and phosphorylation of cyclin D1 at Thr 286, which is known to be required for cyclin D1 proteolysis. The involvement of the DDR in oncogene-induced senescence prompted us to investigate the role of FBXO31 in DNA repair. We find that DNA damage induced by gamma-irradiation results in increased FBXO31 levels, which requires phosphorylation of FBXO31 by the DDR-initiating kinase ATM. RNAi-mediated knockdown of FBXO31 prevents cells from undergoing efficient arrest in G1 after gamma-irradiation and markedly increases sensitivity to DNA damage. Finally, we show that a variety of DNA damaging agents all result in a large increase in FBXO31 levels, indicating that induction of FBXO31 is a general response to genotoxic stress. Our results reveal FBXO31 as a regulator of the G1/S transition that is specifically required for DNA damage-induced growth arrest.
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PMID:F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage. 1941 62

The interferon regulated transcription factor IRF-1 is a tumour suppressor protein that is activated in response to viral infection and cell signalling activated by double stranded DNA lesions. IRF-1 has a short half-life (t(0.5) 20-40 min) allowing rapid changes in steady state levels by modulating its rate of degradation and/or synthesis. However, little is known about the pathway(s) leading to IRF-1 protein degradation or what determines the rate of degradation in cells. Here we establish a role for discrete motifs in the enhancer domain of IRF-1 in directing polyubiquitination and degradation. By studying the structure of the enhancer domain as related to its role in the turnover of IRF-1 we have demonstrated that this region is not subject to modification by ubiquitin but rather that it contains both an ubiquitination signal and a distinct degradation signal. Removal of the C-terminal 70 amino acids from IRF-1 inhibits both its degradation and polyubiquitination, whereas removal of the C-terminal 25 amino acids inhibits degradation of the protein but does not prevent its ubiquitination. Furthermore, consistent with the C-terminus being involved in targeting or recognition by an E3-ligase or associated protein(s) the enhancer domain can act in trans to inhibit IRF-1 ubiquitination by endogenous E3-ligase activity. The identification of structural determinants that signals IRF-1 polyubiquitination and which can be uncoupled from IRF-1 degradation lends support to the idea that the degradation of selective substrates can be regulated at multiple steps in the ubiquitin-proteasome system.
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PMID:Role of the IRF-1 enhancer domain in signalling polyubiquitination and degradation. 1945 Jun 80

The Wnt/beta-catenin signalling pathway has important roles in normal cellular proliferation, development and angiogenesis. Many malignant transformations, including sporadic colorectal tumours, are caused by constitutive activation of the Wnt route due to mutations in the tumour suppressor protein adenomatous polyposis coli (APC) or the beta-catenin oncogene, ultimately resulting in reduced beta-catenin degradation by the ubiquitin (Ub) proteasome system (UPS). The COP9 signalosome (CSN) regulates the UPS by controlling cullin-RING Ub ligases (CRLs). We show here that the CSN and the beta-catenin destruction complex cooperate in targeting beta-catenin for degradation by the UPS. Together with the CRL that ubiquitinates beta-catenin, they form a supercomplex responsible for beta-catenin degradation. Wnt3A, glycogen synthase kinase 3beta inhibitors or mutation of CSN-mediated deneddylation induce the disassembly of the supercomplex and the accumulation of beta-catenin. Likewise, downregulation of the CSN in HeLa cells leads to retarded degradation of beta-catenin. Additionally, we found that the knockdown of the CSN causes accelerated proteolysis of APC, an essential component of the beta-catenin destruction complex, which is degraded by the UPS as beta-catenin. We show here that APC is stabilised by the Ub-specific protease 15 (USP15) associated with the CSN. This is demonstrated by over-expression of siRNA oligonucleotides against USP15 or by over-expression of an USP15 mutant, which is unable to degrade poly-Ub chains. Thus, the CSN controls the Wnt/beta-catenin signalling by assisting the assembly of beta-catenin-degrading supercomplexes by deneddylation and, simultaneously, by stabilising APC via CSN-associated USP15. The CSN regulates the balance between beta-catenin and APC. Disturbance of this balance can cause cancer by driving cell transformation, tumour angiogenesis and metastasis. A model is provided that proposes a role of CSN-mediated deneddylation in the formation of the beta-catenin-degrading supercomplex and the protection of complex-bound APC via CSN-associated USP15.
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PMID:The COP9 signalosome mediates beta-catenin degradation by deneddylation and blocks adenomatous polyposis coli destruction via USP15. 1957 24

Cdx2 is a homeodomain transcription factor that regulates normal intestinal cell differentiation. Cdx2 is frequently lost during progression of colorectal cancer (CRC) and is widely viewed as a colorectal tumour suppressor. A previous study suggested that activation of protein kinase C (PKC) may be responsible for Cdx2 down-regulation in CRC cells. Here we show that activation of PKC does indeed promote down-regulation of Cdx2 at both the mRNA and protein levels. However, PKC-dependent loss of Cdx2 is dependent upon activation of the Raf-MEK-ERK1/2 pathway. Indeed, specific activation of the ERK1/2 pathway using the conditional kinase DeltaRaf-1:ER is sufficient to inhibit Cdx2 transcription. The Raf-MEK-ERK1/2 pathway is hyper-activated in a large fraction of colorectal cancers due to mutations in K-Ras and we show that treatment of CRC cell lines with MEK inhibitors causes an increase in Cdx2 expression. Furthermore, activation of the ERK1/2 pathway promotes the phosphorylation and proteasome-dependent degradation of the Cdx2 protein. The inhibitory effect of ERK1/2 upon Cdx2 in CRC cells is in sharp contrast to its stimulatory effect upon Cdx2 expression in trophectoderm and trophoblast stem cells. These results provide important new insights into the regulation of the Cdx2 tumour suppressor by linking it to ERK1/2, a pathway which is frequently activated in CRC.
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PMID:Down-regulation of Cdx2 in colorectal carcinoma cells by the Raf-MEK-ERK 1/2 pathway. 1968 45

Ubiquitination plays a key role in regulating the tumour suppressor p53. It targets p53 for degradation by the 26S proteasome. The ubiquitin pathway also regulates the activity and localisation of p53. Ubiquitination requires ubiquitin-activating and -conjugating enzymes and ubiquitin ligases. In addition, ubiquitination can be reversed by the action of deubiquitinating enzymes. Here we give an overview of the role of components of the ubiquitin-proteasome system in the regulation of p53 and review progress in targeting these proteins to activate wild-type p53 for the treatment of cancer.
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PMID:Targeting the ubiquitin-proteasome system to activate wild-type p53 for cancer therapy. 1989 40

The p53 tumour suppressor is a tightly controlled transcription factor that coordinates a broad programme of gene expression in response to various cellular stresses leading to the outcomes of growth arrest, senescence, or apoptosis. MDM2 is an E3 ubiquitin ligase that plays a key role in maintaining p53 at critical physiological levels by targeting it for proteasome-mediated degradation. Expression of the MDM2 gene is p53-dependent and thus p53 and MDM2 operate within a negative feedback loop in which p53 controls the levels of its own regulator. Induction and activation of p53 involves mainly the uncoupling of p53 from its negative regulators, principally MDM2 and MDMX, an MDM2-related and -interacting protein that inhibits p53 transactivation function. MDM2 is tightly regulated through various mechanisms including gene expression, protein turnover (mediated by auto-ubiquitylation), protein-protein interaction with key regulators, and post-translational modification, mainly, but not exclusively, by multisite phosphorylation. The purpose of the present article is to review our current knowledge of the signalling mechanisms that focus on MDM2, and indeed MDMX, through both phosphorylation mechanisms and peptide-docking events and to consider the wider implications of these regulatory events in the context of coordinated regulation of the p53 response. This analysis also provides an opportunity to consider the signalling pathways regulating MDM2 as potential targets for non-genotoxic therapies aimed at restoring p53 function in tumour cells.
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PMID:The regulation of MDM2 by multisite phosphorylation--opportunities for molecular-based intervention to target tumours? 1989 41

Arkadia is a positive regulator of transforming growth factor-beta (TGF-beta) signalling, which induces ubiquitylation and proteasome-dependent degradation of negative regulators of the TGF-beta signalling pathway, i.e. Smad7, c-Ski and SnoN. In the present study, we examined the roles of Arkadia in human cancer cells. We first examined the expression of Arkadia in 20 cancer cell lines and 2 non-cancerous cell lines, and found that it was expressed ubiquitously at both the mRNA and protein levels. Interestingly, levels of expression of c-Ski protein, one of the substrates of Arkadia, were not correlated with those of c-Ski mRNA. Arkadia induced down-regulation of c-Ski protein expression in many cell lines examined, but did not in certain cell lines with high levels of expression of c-Ski protein. We also found that knockdown of Arkadia attenuated the induction of TGF-beta target genes, whereas ectopically expressed Arkadia enhanced it. Notably, over-expression of Arkadia inhibited the growth of HepG2 cells in the presence as well as the absence of TGF-beta stimulation. Arkadia thus regulates the levels of expression of c-Ski protein in cell-type-dependent fashion, and exhibits a tumour suppressor function by inhibiting tumour cell growth.
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PMID:Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells. 1995 2

The forkhead box (FOX) proteins are transcription factors that play complex and important roles in processes from development and organogenesis to regulation of metabolism and the immune system. There are 50 FOX genes in the human genome and 44 in the mouse, divided into 19 subfamilies. All human FOX genes have close mouse orthologues, with one exception: the mouse has a single Foxd4 , whereas the human gene has undergone a recent duplication to a total of seven ( FOXD4 and FOXD4L1 --> FOXD4L6 ). Evolutionarily ancient family members can be found as far back as the fungi and metazoans. The DNA-binding domain, the forkhead domain, is an example of the winged-helix domain, and is very well conserved across the FOX family and across species, with a few notable exceptions in which divergence has created new functionality. Mutations in FOX genes have been implicated in at least four familial human diseases, and differential expression may play a role in a number of other pathologies - ranging from metabolic disorders to autoimmunity. Furthermore, FOX genes are differentially expressed in a large number of cancers; their role can be either as an oncogene or tumour suppressor, depending on the family member and cell type. Although some drugs that target FOX gene expression or activity, notably proteasome inhibitors, appear to work well, much more basic research is needed to unlock the complex interplay of upstream and downstream interactions with FOX family transcription factors.
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PMID:Update of human and mouse forkhead box (FOX) gene families. 2065 Aug 21


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