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)

Several regulators of endocytic trafficking have recently been identified as tumour suppressors in Drosophila. These include components of the endosomal sorting complex required for transport (ESCRT) machinery. Disruption of subunits of ESCRT-I and -II leads to cell-autonomous endosomal accumulation of ubiquitinated receptors, loss of apicobasal polarity and epithelial integrity, and increased cell death. Here we report that disruption of the ATPase dVps4, the most downstream component of the ESCRT machinery, causes the same array of cellular phenotypes. We find that loss of epithelial integrity and increased apoptosis, but not loss of cell polarity, require the activation of JNK signalling. Abrogation of JNK signalling prevents apoptosis in dVps4 deficient cells. Indeed double deficiency in dVps4 and JNK signalling leads to the formation of neoplastic tumours. We conclude that dvps4 is a tumour suppressor in Drosophila and that JNK is central to the cell-autonomous phenotypes of ESCRT-deficient cells.
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PMID:Disruption of Vps4 and JNK function in Drosophila causes tumour growth. 1919 1

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

The cascade comprising Raf, mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) is a therapeutic target in human cancers with deregulated Ras signalling, which includes tumours that have inactivated the Nf1 tumour suppressor. Nf1 encodes neurofibromin, a GTPase-activating protein that terminates Ras signalling by stimulating hydrolysis of Ras-GTP. We compared the effects of inhibitors of MEK in a myeloproliferative disorder (MPD) initiated by inactivating Nf1 in mouse bone marrow and in acute myeloid leukaemias (AMLs) in which cooperating mutations were induced by retroviral insertional mutagenesis. Here we show that MEK inhibitors are ineffective in MPD, but induce objective regression of many Nf1-deficient AMLs. Drug resistance developed because of outgrowth of AML clones that were present before treatment. We cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1, Rasgrp4 and Mapk14, which encodes p38alpha. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. This approach represents a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance.
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PMID:Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. 1972 76

Oncogenic Ras mutations render the protein constitutively active and promote tumorigenesis via chronic stimulation of effector pathways. In A549 lung adenocarcinoma approx. 50% of the total Ras population is constitutively active, yet these cells display only weak activation of the effectors: ERK1/2 (extracellular-signal-regulated kinase 1/2) and Akt. In order to identify key negative regulators of oncogenic Ras signalling we performed a phosphatome RNAi (RNA interference) screen in A549 cells and ranked their effects on phosphorylation of Ser473 of Akt. As expected, the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) emerged as a leading hit: knockdown elevated Akt activation to 70% of maximal generated by acute EGF (epidermal growth factor) stimulation. Importantly, we identified other phosphatases with similar potencies including PTPN2 (T-cell protein tyrosine phosphatase; also known as TC-PTP) and PTPRJ (protein tyrosine phosphatase receptor type J; also known as DEP-1/CD148). Potentiation of Akt phosphorylation by knockdown of PTEN or PTPRJ was contingent on the presence of oncogenic K-Ras. Our data reveal a synergy between oncogene function and the loss of a tumour suppressor within the same pathway that was necessary for full effector activation since each alone failed to elicit significant Akt phosphorylation. Taken together, these data reveal potent regulators of Akt signalling which contribute to ameliorating the consequences of oncogenic K-Ras activity.
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PMID:Phosphatome profiling reveals PTPN2, PTPRJ and PTEN as potent negative regulators of PKB/Akt activation in Ras-mutated cancer cells. 1992 11

Constitutive MAPK signalling is observed in approximately 50% of acute myeloid leukaemia (AML) cases. JNK activation in particular is associated with treatment failure in AML. Tribbles proteins (trb-1, trb-2 and trb-3) are potent negative regulators of MAPK pathways influencing apoptosis, differentiation and cell-cycle progression. Here we aimed to examine tribbles gene expression in AML and to characterise their role in leukaemic cells. A microarray dataset was interrogated for tribbles expression levels in AML cases and healthy controls. Myeloid cell proliferation and apoptosis were assayed in response to trb-1/trb-2 gene knockdown and overexpression, as well as a physical and functional interaction between trb and C/EBPalpha. Trb-2 expression was reduced in AML compared to healthy controls (correlating with nucleophosmin (NPM1) mutations), while low trb-1 expression was associated with inactive C/EBPalpha. In vitro assays indicated that trb-1/trb-2 are growth restrictive and pro-apoptotic in Me-1 cells, each capable of inhibiting JNK activation. JNK inactivation was itself associated with reduced Bcl-2 Ser70 phosphorylation, a residue which, when phosphorylated, maintains the anti-apoptotic activity of Bcl-2. Consistent with this, tribbles-mediated dephosphorylation of Bcl-2 Ser70 was associated with subsequent apoptosis. Trb-1/trb-2 transcription appeared to be moderately C/EBPalpha-responsive, and physical interaction between C/EBPalpha and trb-1/trb-2 was observed, suggesting a potential for auto-regulation of trb-1 and trb-2 transcription. In conclusion, we propose that trb-1 and trb-2 tumour suppressor activity may be abrogated in a proportion of AML patients. This may lead to enhanced cell survival, and therefore contribute to pathogenesis of the disease. Trb-1/trb-2 may, therefore, represent useful therapeutic targets for the treatment of AML in patients with dys-regulated trb activity.
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PMID:Tribbles-1 and -2 are tumour suppressors, down-regulated in human acute myeloid leukaemia. 2000 59

Human tumours have a large degree of cellular and genetic heterogeneity. Complex cell interactions in the tumour and its microenvironment are thought to have an important role in tumorigenesis and cancer progression. Furthermore, cooperation between oncogenic genetic lesions is required for tumour development; however, it is not known how cell interactions contribute to oncogenic cooperation. The genetic techniques available in the fruitfly Drosophila melanogaster allow analysis of the behaviour of cells with distinct mutations, making this the ideal model organism with which to study cell interactions and oncogenic cooperation. In Drosophila eye-antennal discs, cooperation between the oncogenic protein Ras(V12) (ref. 5) and loss-of-function mutations in the conserved tumour suppressor scribbled (scrib) gives rise to metastatic tumours that display many characteristics observed in human cancers. Here we show that clones of cells bearing different mutations can cooperate to promote tumour growth and invasion in Drosophila. We found that the Ras(V12) and scrib(-) mutations can also cause tumours when they affect different adjacent epithelial cells. We show that this interaction between Ras(V12) and scrib(-) clones involves JNK signalling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines, a compensatory growth mechanism for tissue homeostasis. The development of Ras(V12) tumours can also be triggered by tissue damage, a stress condition that activates JNK signalling. Given the conservation of the pathways examined here, similar cooperative mechanisms could have a role in the development of human cancers.
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PMID:Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. 2819 13

Urothelial carcinoma (UC) is the most common type of bladder cancer in Western nations. Most patients present with the non-muscle-invasive (NMIUC) form of the disease, while up to a third harbour the invasive form (MIUC). Specifically, the aetiology of NMIUC appears to be multifactorial and very different from that of MIUC. Loss of specific tumour suppressor genes as well as gain-of-function mutations in proteins within defined cellular signalling pathways have been implicated in NMIUC aetiology. The regions of chromosome 9 that harbour CDKN2A, CDKN2B, TSC1, PTCH1 and DBC1 are frequently mutated in NMIUC, resulting in functional loss; in addition, HRAS and FGFR3, which are both proto-oncogenes encoding components of the Ras-MAPK signalling pathway, have been found to harbour activating mutations in a large number of NMIUCs. Interestingly, some of these molecular events are mutually exclusive, suggesting functional equivalence. Since several of these driving changes are amenable to therapeutic targeting, understanding the signalling events in NMIUC may offer novel approaches to manage the recurrence and progression of this disease.
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PMID:Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC). 2033 6

Dual specificity phosphatases are characterised by their ability to dephosphorylate both phosphotyrosine and phosphoserine/threonine residues within the one substrate. The aim of this study was to characterise the phosphatase activity of the atypical dual specificity phosphatase, DUSP26 on MAP kinases, and to determine its expression, regulation and function in cancer cells. Overexpression and knockdown of DUSP26 in epithelial cells and in vitro phosphatase assays were used to demonstrate that, contrary to several published reports, DUSP26 does not act as a dual specificity phosphatase on ERK, JNK or p38 MAPKs. However, overexpression of DUSP26 in MCF10A epithelial cells suppressed colony formation and acinar growth in 3D culture, effects dependent on its phosphatase activity, while knockdown of DUSP26 in HOSE17.1 cells enhanced colony formation and cellular proliferation. DUSP26 mRNA expression was reduced in neuroblastoma, brain and ovarian cancer cell lines. Consistent with epigenetic silencing of DUSP26, expression was enhanced by treatment of cells with 5-aza-2-deoxycitidine and trichostatin A, and a CpG island upstream of the DUSP26 transcriptional start site was variably methylated in cancer cell lines. Together, these results help to clarify confusion in the literature relating to DUSP26 substrate specificity and support recent reports that substrates other than MAPKs are the primary substrates of this phosphatase. In addition, they indicate that DUSP26 may function as a tumour suppressor in particular cancers.
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PMID:DUSP26 negatively affects the proliferation of epithelial cells, an effect not mediated by dephosphorylation of MAPKs. 2034 85

Protein phosphatase 2A (PP2A), in its activated form as a phosphatase, is a tumour suppressor. However, when PP2A is phosphorylated at the tyrosine residue (pY307), it loses its phosphatase activity and becomes inactivated. In our previous study, we found a higher expression of pY307-PP2A in HER-2/neu positive breast tumour samples and significantly correlated to tumour progression, and in this context, it could function as a proto-oncogene. The above and subsequent findings led us to postulate that the critical role of PP2A in maintaining the balance between cell survival and cell death may be linked to its phosphorylation status at its Y307 residue. Hence, we further investigated the effects of knocking down the PP2A catalytic subunit which contains the Y307 amino acid residue in two HER-2/neu positive breast cancer cell lines, BT474 and SKBR3. We showed that this causes the silenced HER-2/neu breast cancer cells to undergo apoptosis and furthermore, that such apoptosis is mediated by p38 MAPK-caspase 3/PARP activation. Understanding the role of PP2A in HER2/neu positive cells might thus provide insight into new targets for breast cancer therapy.
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PMID:Silencing of the PP2A catalytic subunit causes HER-2/neu positive breast cancer cells to undergo apoptosis. 2055 58

The JNKs (c-Jun N-terminal kinases) are stress-activated serine/threonine kinases that can regulate both cell death and cell proliferation. We have developed a cell system to control JNK re-expression at physiological levels in JNK1/2-null MEFs (murine embryonic fibroblasts). JNK re-expression restored basal and stress-activated phosphorylation of the c-Jun transcription factor and attenuated cellular proliferation with increased cells in G1/S-phase of the cell cycle. To explore JNK actions to regulate cell proliferation, we evaluated a role for the cytosolic protein, STMN (stathmin)/Op18 (oncoprotein 18). STMN, up-regulated in a range of cancer types, plays a crucial role in the control of cell division through its regulation of microtubule dynamics of the mitotic spindle. In JNK1/2-null or c-Jun-null MEFs or cells treated with c-Jun siRNA (small interfering RNA), STMN levels were significantly increased. Furthermore, a requirement for JNK/cJun signalling was demonstrated by expression of wild-type c-Jun, but not a phosphorylation-defective c-Jun mutant, being sufficient to down-regulate STMN. Critically, shRNA (small hairpin RNA)-directed STMN down-regulation in JNK1/2-null MEFs attenuated proliferation. Thus JNK/c-Jun regulation of STMN levels provides a novel pathway in regulation of cell proliferation with important implications for understanding the actions of JNK as a physiological regulator of the cell cycle and tumour suppressor protein.
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PMID:c-Jun N-terminal kinase/c-Jun inhibits fibroblast proliferation by negatively regulating the levels of stathmin/oncoprotein 18. 2059 88


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