Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor p53 protein suppresses cell growth by inducing cell cycle arrest or apoptosis. Despite the fact that p53-dependent p21-mediated G1 arrest induced by DNA damage is well defined, the role of p53 in the cell cycle in response to the MAKP signaling remains to be determined. Here we show that MKP1, a member of the dual specificity protein phosphatase family capable of inactivating MAPKs, is a transcriptional target of p53. MKP1 mRNA and protein levels were increased upon p53 activation in several well defined p53-regulated cell systems. p53 bound to a consensus p53 binding site located in the second intron of the MKP1 gene and transactivated MKP1 in reporter gene assays. Inhibition of phosphatase activity impaired p53-mediated G1 arrest in arrested human glioblastoma GM cells in response to growth factor stimuli. Importantly conditional expression of MKP1 prevented arrested human cancer cells from entering into the cell cycle. Thus, these results provide a novel mechanism by which p53 controls the cell cycle in response to the MAPK signaling in the absence of DNA damage and suggest that p53 may negatively control the MAKP pathway via MKP1.
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PMID:The phosphatase MKP1 is a transcriptional target of p53 involved in cell cycle regulation. 1289 Jun 71

PTEN, on 10q23.3, encodes a major lipid phosphatase which signals down the phosphoinositol-3-kinase/Akt pathway and effects G1 cell cycle arrest and apoptosis. Germline PTEN mutations have been found to occur in 80% of classic Cowden syndrome (CS), 60% of Bannayan-Riley-Ruvalcaba syndrome (BRRS), up to 20% of Proteus syndrome (PS), and approximately 50% of a Proteus-like syndrome (PSL). CS is a heritable multiple hamartoma syndrome with a high risk of breast, thyroid, and endometrial carcinomas. BRRS is a congenital autosomal dominant disorder characterized by megencephaly, developmental delay, lipomatosis, and speckled penis. PS and PSL had never been associated with risk of malignancy. Finding germline PTEN mutations in patients with BRRS, PS, and PSL suggests equivalent risks of developing malignancy as in CS with implications for medical management. The mutational spectra of CS and BRRS overlap, with many of the mutations occurring in exons 5, 7, and 8. Genotype-phenotype association analyses have revealed that the presence of germline PTEN mutations is associated with breast tumor development, and that mutations occurring within and 5' of the phosphatase motif were associated with multi-organ involvement. Pooled analysis of PTEN mutation series of CS and BRRS occurring in the last five years reveals that 65% of CS-associated mutations occur in the first five exons encoding the phosphatase domain and the promoter region, while 60% of BRRS-associated mutations occur in the 3' four exons encoding mainly the C2 domain. Somatic PTEN mutations occur with a wide distribution of frequencies in sporadic primary tumors, with the highest frequencies in endometrial carcinomas and glioblastoma multiform. Several mechanisms of PTEN inactivation occur in primary malignancies derived from different tissues, but a favored mechanism appears to occur in a tissue-specific manner. Inappropriate subcellular compartmentalization and increased/decreased proteosome degradation may be two novel mechanisms of PTEN inactivation. Further functional work could reveal more effective means of molecular-directed therapy and prevention.
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PMID:PTEN: one gene, many syndromes. 1293 83

Dual-specificity phosphatase 5 (DUSP5), a VH1-like enzyme that hydrolyses nuclear substrates phosphorylated on both tyrosine and serine/threonine residues, has a potential role in deactivation of mitogen- or stress-activated protein kinases. Using cDNA-microarray technology, we found that the expression of DUSP5 mRNA was dramatically increased by exogenous p53 in U373MG, a p53-mutant glioblastoma cell line. Transcription of DUSP5 was also remarkably activated by endogenous p53 in response to DNA damage in colon-cancer cells (p53+/+) that contained wild-type p53, but not in p53-/- cells. Chromatin-immunoprecipitation (ChIP) and reporter assays demonstrated that endogenous p53 protein would bind directly to the promoter region of the DUSP5 gene, implying p53-dependent transcriptional activity. Overexpression of DUSP5 suppressed the growth of several types of human cancer cells, in which Erk1/2 was significantly dephosphorylated. If, as the results suggest, DUSP5 is a direct target of p53, it represents a novel mechanism by which p53 might negatively regulate cell-cycle progression by downregulating mitogen- or stress-activated protein kinases.
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PMID:Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target of tumor suppressor p53. 1294 6

Glioblastomas frequently carry mutations in the PTEN tumor suppressor gene on 10q23.3. The tumor suppressor properties of Pten are closely related to its inhibitory effect on the phosphatidyl-inositol-3'-kinase (Pi3k)-dependent activation of protein kinase B (Akt) signalling. Here, we report on the analysis of 17 genes related to the Pi3k/Akt signalling pathway for genetic alteration and aberrant expression in a series of 103 glioblastomas. Mutation, homozygous deletion or loss of expression of PTEN was detected in 32% of the tumors. In contrast, we did not find any aberrations in the inositol polyphosphate phosphatase like-1 gene (INPPL1), whose gene product may also counteract Pi3k-dependent Akt activation. Analysis of genes encoding proteins that may activate the pathway upstream of Pi3k revealed variable fractions of tumors with EGFR amplification (31%), PDGFRA amplification (8%), and IRS2 amplification (2%). The protein tyrosine kinase 2 (PTK2/FAK1) gene was neither amplified nor overexpressed at the mRNA level. Investigation of three genes encoding catalytic subunits of Pi3k (PIK3CA, PIK3CD, and PIK3C2B) revealed amplification of PIK3C2B (1q32) in 6 tumors (6%). Overexpression of PIK3C2B mRNA was detected in 4 of these cases. PIK3CD (1p36.2) and PIK3CA (3q26.3) were not amplified but PIK3CD mRNA was overexpressed in 6 tumors (6%). Amplification and overexpression of AKT1 was detected in a single case of gliosarcoma. The IRS1, PIK3R1, PIK3R2, AKT2, AKT3, FRAP1, and RPS6KB1 genes were neither amplified nor overexpressed in any of the tumors. Taken together, our data indicate that different genes related to the Pi3k/Akt signalling pathway may be aberrant in glioblastomas.
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PMID:Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. 1465 56

The transcription factor nuclear factor kappaB (NF-kappaB) plays an important role in inflammation and cancer, is activated by a variety of stimuli including tumor necrosis factor alpha, interleukin-1, UV irradiation, and viruses, as well as receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR). Although previous studies suggest that EGFR can induce NF-kappaB, the mechanism of this activation remains unknown. In this study, we identify the components of the EGFR-induced signalosome in human glioblastoma cells required to regulate NF-kappaB activation. Immunoprecipitation analyses with ErbB-modulated cells indicate that association between SHP-2 and Grb2-associated binder 1 (Gab1) is the critical step in the formation of the signalosome linking EGFR to NF-kappaB activation. We also show that EGFR-induced NF-kappaB activation is mediated by the PI3-kinase/Akt activation loop. Overexpression of SHP-2, Gab1, and myristoylated Akt significantly upregulated NF-kappaB transcriptional activity and DNA binding activity in glioblastoma cells. Interestingly, overexpression of either one of the two SH2 domain mutants of SHP-2, R32E or R138E, slightly reduced NF-kappaB activity relative to that of wild-type SHP-2, indicating that the SH2 domains of SHP-2 are required for EGFR-induced NF-kappaB activation. On the other hand, ectopic overexpression of either a Gab1 mutant incapable of binding to SHP-2 (Y627F) or a phosphatase-inactive SHP-2 mutant (C459S) caused a significant increase in NF-kappaB activity. Moreover, SHP-2 C459S-expressing cells displayed higher Gab1 phosphotyrosine content, suggesting that SHP-2 regulates Gab1 phosphorylation through its phosphatase domain, which confers a negative regulatory effect on NF-kappaB activity. These results indicate that SHP-2/Gab1 association is critical for linking EGFR to NF-kappaB transcriptional activity via the PI3-kinase/Akt signaling axis in glioblastoma cells and that SHP-2 acts as a dual regulator of NF-kappaB activation.
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PMID:Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB activation through Gab1 in glioblastoma cells. 1470 53

The PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour-suppressor protein is a phosphoinositide 3-phosphatase which antagonizes phosphoinositide 3-kinase-dependent signalling by dephosphorylating PtdIns(3,4,5)P3. Most tumour-derived point mutations of PTEN induce a loss of function, which correlates with profoundly reduced catalytic activity. However, here we characterize a point mutation at the N-terminus of PTEN, K13E from a human glioblastoma, which displayed wild-type activity when assayed in vitro. This mutation occurs within a conserved polybasic motif, a putative PtdIns(4,5)P2-binding site that may participate in membrane targeting of PTEN. We found that catalytic activity against lipid substrates and vesicle binding of wild-type PTEN, but not of PTEN K13E, were greatly stimulated by anionic lipids, especially PtdIns(4,5)P2. The K13E mutation also greatly reduces the efficiency with which anionic lipids inhibit PTEN activity against soluble substrates, supporting the hypothesis that non-catalytic membrane binding orientates the active site to favour lipid substrates. Significantly, in contrast to the wild-type enzyme, PTEN K13E failed either to prevent protein kinase B/Akt phosphorylation, or inhibit cell proliferation when expressed in PTEN-null U87MG cells. The cellular functioning of K13E PTEN was recovered by targeting to the plasma membrane through inclusion of a myristoylation site. Our results establish a requirement for the conserved N-terminal motif of PTEN for correct membrane orientation, cellular activity and tumour-suppressor function.
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PMID:The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif. 1471 68

Receptor tyrosine kinases (RTK) and the tumor suppressor PTEN co-regulate oncogenic cell signaling pathways. How these interactions influence gene transcription is inadequately understood. We used expression microarrays to investigate the effects of PTEN on gene expression changes caused by activating c-Met in human glioblastoma cells. c-Met activation by scatter factor/hepatocyte growth factor (SF/HGF) altered the expression of 27-fold more genes in PTEN-null U-373MG cells than in PTEN homozygous primary normal human astrocytes (523 vs 19 genes). Restoring wt-PTEN in U-373MG cells dramatically altered patterns of c-Met regulated gene expression. This effect was varied depending on the specific gene in question. PTEN reduced the number of c-Met regulated transcripts from 931 to 502, decreased the relative number of genes upregulated by c-Met from 46 to 25%, and increased the relative number of downregulated genes from 54 to 75%. PTEN and c-Met co-regulated many genes involved in cell growth regulation such as oncogenes, growth factors, transcription factors, and constituents of the ubiquitin pathway. c-Met activation in PTEN-null (but not PTEN reconstituted) cells led to upregulation of the EGFR agonist TGFalpha and subsequently to EGFR activation. Using PTEN mutants, we found that PTEN's transcriptional effects were either lipid-phosphatase dependent, protein-phosphatase dependent, or phosphatase-independent. These results show that PTEN has critical and mechanistically complex effects on RTK-regulated gene transcription. These findings expand our understanding of tumor promoter/suppressor inter-relationships and downstream transcriptional effects of PTEN loss and c-Met overexpression in malignant gliomas.
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PMID:Regulation of c-Met-dependent gene expression by PTEN. 1551 82

The small GTPase Rac1 is thought to play an important role in cell migration and invasion. We have previously identified synaptojanin 2, a phosphoinositide phosphatase, as an effector of Rac1. Here, we show that small interfering RNA-mediated depletion of either Rac1 or synaptojanin 2 inhibits invasion of SNB19 and U87MG glioblastoma cells through Matrigel and rat brain slices. Depletion of Rac1 or synaptojanin 2 also inhibits migration of SNB19 and U87MG cells on glioma-derived extracellular matrix. In addition, we found that depletion of Rac1 or synaptojanin 2 inhibits the formation of lamellipodia and invadopodia, specialized membrane structures that are thought to be involved in extracellular matrix degradation. These results suggest that synaptojanin 2 contributes to the role of Rac1 in cell invasion and migration by regulating the formation of invadopodia and lamellipodia. This study also identifies synaptojanin 2 as a novel potential target for therapeutic intervention in malignant tumors.
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PMID:Role of synaptojanin 2 in glioma cell migration and invasion. 1554 94

In human glioblastomas, the most common mutation of epidermal growth factor receptor (EGFR) is an in-frame deletion of an 801-bp sequence in the extracellular domain of EGFR termed EGFRvIII. The EGFRvIII does not bind ligand EGF but has constitutive tyrosine phosphorylation (pTyr) content and kinase activity that result in enhanced transformation, reduced apoptosis, and resistance to therapy. Here we report that the protein tyrosine phosphatase SHP-2 modulates a mitogen-activated protein kinase (MAPK) kinase (MEK)-mediated signaling pathway that regulates EGFRvIII pTyr and cell survival in U87MG.EGFRvIII cells. Overexpression of the phosphatase-inactive form of SHP-2 inhibited EGFRvIII pTyr by decreasing MAPK phosphorylation. Consistent with this, we observed that the MEK inhibitor PD98059, but not the phosphatidylinositol 3'-kinase inhibitor LY294002, inhibited EGFRvIII pTyr. Furthermore, constitutive EGFRvIII pTyr content observed in U87MG, LN229, and U373MG glioblastoma cells, but not in NR6.EGFRvIII fibroblasts, correlated with elevated MAPK levels in these cells. Interestingly, LY294002, but not PD98059, inhibited wild-type EGFR pTyr in response to EGF treatment in U87MG parental cells and in wild-type EGFR-overexpressing U87MG cells. Inhibition of EGFRvIII pTyr by PD98059 was not observed to be phosphorylation site specific. However, LY294002 more specifically inhibited wild-type EGFR pTyr at residues Tyr(992) and Tyr(1068) in the COOH terminus. Treatment of U87MG.EGFRvIII cells with PD98059, but not LY294002, also resulted in increased cell death in response to cisplatin. Collectively, a distinct MEK-mediated pathway in human glioblastoma cells appears to differentially modulate EGFRvIII and wild-type EGFR pTyr, and inhibition of the MAPK pathway sensitizes EGFRvIII-containing human glioblastoma cells to cisplatin-induced cell death.
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PMID:SHP-2-dependent mitogen-activated protein kinase activation regulates EGFRvIII but not wild-type epidermal growth factor receptor phosphorylation and glioblastoma cell survival. 1554 97

The tumor suppressor gene phosphatase and tensin homologue (PTEN) regulates the phosphatidylinositol-3'-kinase (PI3K) signaling pathway and has been shown to correlate with poor prognosis in high-grade astrocytomas when mutational inactivation or loss of the PTEN gene occurs. PTEN mutation leads to constitutive activation of protein kinase B (PKB)/Akt with phosphorylation at the PKB/Akt sites Thr-308 and Ser-473. Integrin-linked kinase (ILK) has been shown to regulate PKB/Akt activity with the loss of PTEN in prostate cancer. We now demonstrate that ILK activity regulates PKB/Akt activity in glioblastoma cells. The activity of ILK is constitutively elevated in a serum-independent manner in PTEN mutant cells, and transfection of wild-type PTEN under the control of an inducible promoter into mutant PTEN cells inhibits ILK activity. Transfection of ILK antisense (ILKAS) or exposure to a small-molecule ILK inhibitor suppresses the constitutive phosphorylation of PKB/Akt on Ser-473 in PTEN-mutant glioblastoma cell lines. In addition, the delivery of ILKAS to PTEN-negative glioblastoma cells resulted in apoptosis. Rag-2M mice bearing established ( approximately 100 mg) human U87MG glioblastoma tumors, treated QD x 5 for 3 consecutive weeks with ILKAS (i.p. 5 mg/kg), exhibited stable disease with < or =7% increase in tumor volume over the 3-week course of treatment. In contrast, animals treated with an oligonucleotide control or saline exhibited a >100% increase in tumor volume over the same time period. Our initial results indicate that therapeutic strategies targeting ILK may be beneficial in the treatment of glioblastomas.
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PMID:Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. 1578 40


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