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

p21(Cip1/WAF1) (p21), a p53-inducible protein, is a critical regulator of cell cycle and cell survival. p21 binds to and inhibits both the DNA synthesis regulator proliferating cell nuclear antigen and cyclin A/E-CDK2 complexes. Recently, p21 has also been shown to be a positive regulator of cell cycle progression as p21 is necessary for the assembly and activation of cyclin D1-CDK4/6 complexes. Furthermore, elevated p21 protein levels have been observed in various aggressive tumors as well as linked to chemoresistance. Here we demonstrate that p21 is directly phosphorylated by AKT/PKB, a survival kinase that is hyperactivated in many late stage tumors. Two sites (Thr(145) and Ser(146)) in the carboxyl terminus of p21 are phosphorylated by AKT/PKB in vitro and in vivo. Phosphorylation of Thr(145) inhibits PCNA binding, whereas phosphorylation of Ser(146) significantly increases p21 protein stability. Glioblastoma cell lines with activated AKT/PKB show enhanced p21 stability, and they are more resistant to taxol-mediated toxicity. Finally, AKT/PKB controls the assembly of cyclin D1-CDK4 complexes through modulation of p21 and cyclin D1 levels. These data imply that enhanced levels of p21 in tumors are due, in part, to phosphorylation by activated AKT/PKB. Furthermore, they suggest that one mechanism of AKT/PKB regulation of tumor cell survival and/or proliferation is to stabilize p21 protein.
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PMID:AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. 1175 12

Cowden disease is an autosomal dominant inherited cancer syndrome characterized by the occurrence of multiple hamartomas, tumors or hyperplastic lesions that may develop in any organ. The disease is related to germline mutation of the PTEN gene, a recently cloned tumor suppressor gene involved in the pathogenesis of sporadic glioblastoma and endometrial carcinoma. It has been shown that the PTEN gene product was a phosphatase able for dephosphorylating a lipid substrate: the phosphatidylinositol (3,4,5)-triphosphate (PIP3). So PTEN appears to negatively control the PI3K-AKT signaling pathway implicated in regulation of cell growth and survival.
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PMID:[Cowden disease and the PTEN gene: a successfully clinical and biological combined approach]. 1179 8

Resistance to conventional adjuvant therapies (i.e., chemotherapy and radiation) has been well documented in malignant gliomas. Unlike many other tumor types, combined modality therapy involving radiation and chemotherapy has failed to appreciably enhance outcome for glioblastoma patients compared with radiation alone. In vitro, we have observed an actual antagonistic effect between sequential administration of radiation and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy in three primary human glioblastoma cell lines (referred as the GBME3-5 cell lines), which also happen to demonstrate strong expression of the epidermal growth factor receptor (EGFR). Upon inhibition of EGFR with the EGFR tyrosine kinase inhibitor, AG1478, it was found that this cross-resistance between sequential administration of radiation and BCNU was abrogated. To dissect which of these pathways may be responsible for the observed antagonism, known EGFR-regulated downstream signaling pathways including RAS, phosphatidylinositol 3-kinase (PI3-K), mitogen-activated protein kinase (p44/p42), and protein kinase C were inactivated with both pharmacological inhibitors and transient transfection experiments with dominant-negative and constitutively active constructs in the presence of exogenous EGF stimulation. It was found that BCNU inhibited radiation-induced apoptosis through EGFR-mediated activation of PI3-K/AKT via RAS. On the other hand, radiation was found to inhibit BCNU-induced apoptosis through EGFR-mediated activation of both PI3-K and mitogen-activated protein kinase (p44/p42) pathways, also via RAS. Inhibition of either EGFR or RAS activity appears to not only abrogate the observed antagonism between sequentially administered radiation and chemotherapy but actually results in a greater enhancement of apoptosis in the setting of combined modality therapy than when administered with either radiation or chemotherapy as single agents. Therefore, these findings suggest that strategies to inactivate EGFR or RAS signaling may be critical to improving not only the efficacy of single-agent therapy but also of combined modality therapy in gliomas.
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PMID:The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a RAS-dependent manner. 1215 34

Overexpressed epidermal growth receptor factor receptors (EGFRs) are thought to contribute to the malignant phenotype of human glioblastomas (GBMs), but the mechanism is not well understood. We found that SKMG-3 cells, a rare GBM cell line that maintains EGFR gene amplification in vitro, produced high levels of EGFR protein. The cells also expressed the related receptors HER2/neu and HER4, but not HER3. Immunoblots and tryptic phosphopeptide maps showed that the SKMG-3 EGFRs were intact and functional and that a subset of these receptors were spontaneously autophosphorylated. EGF treatment stimulated phosphorylation of the EGFRs as well as the downstream effectors Erk, AKT1, stat3 and c-Cbl. Under minimal growth conditions, the unstimulated SKMG-3 cells contained constitutively phosphorylated Erk and AKTI but no detectable stat3 DNA-binding complexes. The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1. In contrast, inhibition of phosphatidylinositol-3-kinase (PI3K) blocked the constitutive phosphorylation of Erk and AKT-1 but not the EGFR. We conclude that the SKMG-3 cells represent the subset of GBMs with amplified EGFR genes that overexpress intact receptors. The results also suggest that in some GBMs, signals from overexpressed EGFRs contribute to the constitutive phosphorylation of Erk, but these signals may not required for the constitutive activation of PI3K or AKT1.
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PMID:Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells. 1253 15

The granulin-epithelin precursor, progranulin, PC-cell-derived growth factor or acrogranin, is a high molecular weight secreted mitogen. It is abundantly expressed in rapidly cycling epithelial cells, in the immune system and in neurons, such as cerebellar Purkinje cells. Progranulin contributes to tumorigenesis in diverse cancers, including breast cancer, clear cell renal carcinoma, invasive ovarian carcinoma and glioblastoma. It regulates the rate of epithelial cell division in responsive epithelial cells, and confers an invasive phenotype on these cells. It is involved in the wound response. During embryogenesis, progranulin accelerates blastocyst formation, and is a growth factor for trophectodermal cells. In the neonate, progranulin, regulates the hormone-dependent virilization of the hypothalamus. It activates phosphorylation of Shc, and p44/42 MAPK (mitogen activated protein kinase) in the ERK (extracellular regulated kinase) signaling pathway; PI3K (phosophatidyl inositol-3-kinase), AKT/protein kinase B, and p70S6kinase in the phosophatidyl inositol-3-kinase pathway; and focal adhesion kinase in the adhesion/motility pathway. The signaling properties of progranulin are apparently similar to those of classic growth factors, but the functional properties of progranulin distinguish it from these molecules. Deleting the insulin-like growth factor I receptor from murine embryonic fibroblasts blocks proliferation in response to all classic growth factors, such as epidermal growth factor, or platelet-derived growth factor, whereas progranulin retains mitotic activity on these cells. The defined biological actions of progranulin probably represent a small fraction of its overall functions. Transcriptome analyses show that the progranulin gene is induced in numerous situations that vary from obesity to the transcriptional response of cells to antineoplastic drugs. Here, the biological roles of progranulin will be reviewed, with an emphasis on cancer and cell proliferation.
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PMID:Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. 1297 94

Genetic alterations of PI3K (phosphoinositide 3-kinase) subunits have been documented in a number of tumor types, with increased PI3K activity linked to gene amplification and mutation of catalytic subunits, as well as mutations of regulatory subunits. Among high grade gliomas, activation of the PI3K-AKT signaling pathway through loss of PTEN function is common. We therefore investigated whether genetic alteration of class IA PI3Ks might provide a mechanism for deregulation of this pathway in glioblastomas. We studied a series of glioblastomas with FISH to assess copy number of catalytic subunits (PIK3CA and PIK3CD) and with PCR-SSCP to screen for somatic mutations of conserved regions of both catalytic and regulatory subunits. FISH revealed frequent balanced copy number increases of both PIK3CA and PIK3CD, and one case showed an extra copy limited to PIK3CA. One glioblastoma exhibited a 9-bp deletion that encompassed the exon-intron junction of exon 12 of PIK3R1, documenting for the first time a mutation within a PI3K regulatory subunit in human glioblastoma. This deletion would be predicted to yield a truncated protein that lacks the inhibitory domain, resulting in increased PI3K activity. Furthermore, the case with selected PIK3CA copy number gain and the case with a truncating PIK3R1 mutation both featured AKT activation without PTEN mutation. These results suggest that genetic alterations of class IA PI3K subunit genes can occasionally play a role in human glioblastoma by activating the PI3K-AKT signaling pathway independently of PTEN mutation.
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PMID:Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. 1560 84

Gp130-like receptor (GPL) is a newly identified cytokine receptor. A recent study reported the involvement of GPL, together with OSMR, in the formation of the receptor complex for IL-31, a novel immune cytokine with a skin tropism. In the present work, we analyzed the signaling properties of IL-31 in glioblastoma and melanoma tumor cells. We demonstrate that in response to IL-31, its receptor complex recruits Jak1, Jak2, STAT1, -3, -5 signaling pathways, as well as the Pi3 kinase / AKT cascade. SHP-2 and Shc adapter molecules are also recruited and contribute to an increased activation of the MAP kinase pathway in response to IL-31. Different responses were observed depending on the expression of short or long GPL receptor isoform within the studied cell lines. We show that the short form of GPL receptor exerts a profound inhibitory effect on the signaling of IL-31 and behaves as a dominant negative receptor.
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PMID:Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling. 1562 37

Activation of protein kinase Cbeta (PKCbeta) has been repeatedly implicated in tumor-induced angiogenesis. The PKCbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Activation of PKCbeta has now also been implicated in tumor cell proliferation, apoptosis, and tumor invasiveness. Herein, we show that Enzastaurin has a direct effect on human tumor cells, inducing apoptosis and suppressing the proliferation of cultured tumor cells. Enzastaurin treatment also suppresses the phosphorylation of GSK3betaser9, ribosomal protein S6(S240/244), and AKT(Thr308). Oral dosing with Enzastaurin to yield plasma concentrations similar to those achieved in clinical trials significantly suppresses the growth of human glioblastoma and colon carcinoma xenografts. As in cultured tumor cells, Enzastaurin treatment suppresses the phosphorylation of GSK3beta in these xenograft tumor tissues. Enzastaurin treatment also suppresses GSK3beta phosphorylation to a similar extent in peripheral blood mononuclear cells (PBMCs) from these treated mice. These data show that Enzastaurin has a direct antitumor effect and that Enzastaurin treatment suppresses GSK3beta phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK3beta phosphorylation may serve as a reliable pharmacodynamic marker for Enzastaurin activity. With previously published reports, these data support the notion that Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis.
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PMID:The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. 1610

The PTEN tumor suppressor is a central negative regulator of the PI3K/AKT signaling cascade that influences multiple cellular functions including cell growth, survival, proliferation and migration in a context-dependent manner. Dysregulation of this signaling pathway contributes to many cancers in man. PTEN is the most commonly altered component of the PI3K pathway in human malignancies. Mutations occur in both heritable and sporadic settings, with high frequency in sporadic glioblastoma, prostate and endometrial cancer. Data from human tumors and animal models support the concept that the effects of PTEN inactivation are tissue-specific. Elucidation of the mechanisms regulating activation of unique downstream effectors that mediate distinct outcomes of PTEN loss will augment our understanding of tumorigenesis and ultimately lead to novel therapeutic options.
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PMID:PTEN function in normal and neoplastic growth. 1641 71

We employed an in vitro hypoxia cell culture model system and gene transfer technology to examine the effect of the decorin gene on cell survival against oxygen and glucose deprivation (OGD). Ectopic expression of decorin in subventricular zone (SVZ) cells from adult male mouse brain and human glioblastoma U-87 cells kept the cells viable against 24 h of OGD. Fewer than 1% of decorin-synthesizing cells were apoptotic after 12 h of OGD. In contrast, 100% of the control cells were apoptotic even after 4 h of OGD. De novo decorin synthesis in SVZ and U-87 cells induced expression of p21, p27 and Ras, AKT (acutely transforming retrovirus AKT8 in rodent T-cell lymphoma), and phosphorylated AKT. Blocking of phosphoinositide 3-kinase (PI-3K), Ras, and the epidermal growth factor receptor with specific inhibitors had no effect on induction of Ras, p21, and p27 at the messenger RNA level in decorin-synthesizing SVZ and U-87 cells. PI-3K inhibitors significantly increased apoptosis in decorin-expressing cells. Our data indicate that induction of p21, p27, Ras, AKT, and phosphorylated AKT by decorin inhibits apoptosis and protects U-87 and SVZ cells against OGD. Therefore, our data suggest that decorin is a potent trophic factor that protects neuronal progenitor cells and glioma cells from OGD.
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PMID:Protection of adult mouse progenitor cells and human glioma cells by de novo decorin expression in an oxygen- and glucose-deprived cell culture model system. 1646 81


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