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 retinoblastoma tumor suppressor gene product, as well as its related protein p107, has been shown clearly to exert its growth suppressive effects in a cell cycle dependent manner. In this study we demonstrate that the introduction of our recently cloned Rb family member p130/pRb2 causes growth arrest in three tumor cell lines. In addition, in the nasopharyngeal carcinoma derived cell line HONE-1, we identified a low level of expression of p130/pRb2, possibly due to gene rearrangement, and a drastic reduction in proliferation upon introduction of a constitutive active p130/pRb2 complementary DNA clone. Furthermore, we were able to dissect distinct properties of the Rb family by demonstrating that p130/pRb2 inhibits proliferation of the glioblastoma cell line T98G, which is resistant to the growth suppressive effects of both pRb and p107. Our studies demonstrate that the Rb family proteins identified to date may complement each other but they are not fully functionally redundant.
 ...
PMID:p130/pRb2 has growth suppressive properties similar to yet distinctive from those of retinoblastoma family members pRb and p107. 792 96

The mammalian nuclear protein E2F-1 has recently been cloned based on its ability to bind the retinoblastoma protein. To determine whether E2F-1 plays a role in the control of the cell proliferation, we introduced an inducible construct expressing an E2F-1 antisense RNA into the human glioblastoma T98G cell line and assessed DNA synthesis during the cell cycle. Expression of the antisense transcripts during the G1-S transition resulted in a marked delay in the completion of DNA synthesis. Band-shift analysis of bacterially produced E2F-1 showed that this protein bound to the promoters of human DNA polymerase-alpha, cyclin D1, and c-myb but not to the cdc2 gene promoter. E2F-1 also transactivated the bound promoters in transient transfection assays. These results suggest a major role for E2F-1 in the control of cell cycle progression via transcriptional regulation of proliferation-associated genes.
 ...
PMID:Correlation between E2F-1 requirement in the S phase and E2F-1 transactivation of cell cycle-related genes in human cells. 813 37

The retinoblastoma protein family has been implicated in growth control and modulation of the activity of genes involved in cell proliferation, such as B-myb. Recent evidence indicates that the product of the B-myb gene is necessary for the growth and survival of several human and murine cell lines. Upon overexpression, B-myb induces deregulated cell growth of certain cell lines. Here we show that B-myb overexpression is able to induce DNA synthesis in p107 growth-arrested human osteosarcoma cells (SAOS2). p107 might exert its growth-suppressive activity by regulating B-myb gene transcription. Indeed, p107 down-modulated B-myb promoter activity and drastically decreased E2F-mediated transactivation. Finally, B-myb was able to stimulate DNA synthesis of both stably and transiently transfected human glioblastoma cells (T98G). Altogether, these data provide definitive evidence that the human B-myb protein is involved in growth control of human cells, and that p107 has a significant role in regulating B-myb gene activity.
 ...
PMID:B-myb promotes S phase and is a downstream target of the negative regulator p107 in human cells. 862 1

Primary glioblastomas develop rapidly de novo through a genetic pathway characterized by amplification/overexpression of EGFR and of MDM2 genes. Secondary glioblastomas develop more slowly through progression from low grade or anaplastic astrocytoma and show a high incidence of a p53 mutation. In the present study, primary and secondary glioblastomas were analyzed for p16 deletions and CDK4 amplification by differential PCR and for loss of expression of the retinoblastoma (RB) gene by immunohistochemistry. Except for one case, alterations in the structure or expression of p16, CDK4 and RB were mutually exclusive. The overall incidence of aberrant expression of these genes coding for components of the cell-cycling-regulatory system was similar in primary (14/28; 50%) and secondary glioblastomas (9/23; 39%). However, p16 deletions were significantly more frequent in the former (10/28; 36%) than in the latter (1/23, 4%; P = 0.0075), suggesting that this alteration constitutes an additional genetic hallmark of the primary (de novo) glioblastoma.
 ...
PMID:Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. 934 29

The E2F element is a cis-acting DNA sequence within the P2 promoter of c-myc proto-oncogene. While it is required for optimal transcription, the multiprotein complexes formed on this site have not been well characterized. We show that in extracts of human glioblastoma cells and NIH3T3 fibroblasts, significant E2F transcription factor binding to the c-myc E2F site occurs as a both a monomer (the active form) and as only two mutually exclusive complexes with the retinoblastoma gene product (pRb) or the cyclin A protein. The E2F protein monomer was found predominantly in the cytosolic fraction of the cellular extracts while the pRb and cyclin A complexes in the nuclear fraction, indicating that the monomer has novel physical properties. Thus, protein complex formation on the c-myc E2F site appears to contribute in a unique way to transcriptional activation.
 ...
PMID:Multiprotein complex formation on the c-myc promoter. 941 3

Increased protein kinase C(alpha) (PKC(alpha)) expression in glioblastoma cells is associated with proliferation and resistance to drug-induced apoptosis by an undefined anti-apoptotic pathway. To clarify the role of PKC in apoptosis, we have investigated the effect of the selective PKC inhibitor Ro 31-8220 (3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H -pyrrole-2,5-dione methanesulfonate) in two glioblastoma cell lines whose proliferation is dependent on high levels of PKC(alpha). U-87 and A172 cells treated with an IC50 of Ro 31-8220 exhibited nucleosomal DNA fragmentation that coincided with an increase in the number of apoptotic cells. This effect was preceded by the rapid nuclear accumulation of wild-type p53 within 2 hr, and an increased level of the pro-apoptotic protein, insulin-like growth factor-1-binding protein-3, (IGFBP3) but not other p53-regulated proteins such as p21WAF1 or Bax. Accumulation of p53 was also associated with the hypophosphorylated and activated form of the retinoblastoma tumor suppressor protein (RB) at later times after treatment. These results suggest that PKC(alpha) suppresses apoptosis in glioblastoma cells primarily by restricting the accumulation of p53 and the expression of insulin-like growth factor-1-binding protein, as well as by maintaining RB in an inactive hyperphosphorylated state.
 ...
PMID:Induction of apoptosis in glioblastoma cells by inhibition of protein kinase C and its association with the rapid accumulation of p53 and induction of the insulin-like growth factor-1-binding protein-3. 963 8

Genetic alterations in the MMAC1 tumor suppressor gene (also referred to as PTEN or TEP1) occur in several types of human cancers including glioblastoma. Growth suppression induced by overexpression of MMAC1 in cells with mutant MMAC1 alleles is thought to be mediated by the inhibition of signaling through the phosphatidylinositol 3-kinase pathway. However, the exact biochemical mechanisms by which MMAC1 exerts its growth-inhibitory effects are still unknown. Here we report that recombinant adenovirus-mediated overexpression of MMAC1 in three different MMAC1-mutant glioblastoma cell lines blocked progression from G0/G1 to S phase of the cell cycle. Cell cycle arrest correlated with the recruitment of the cyclin-dependent kinase (CDK) inhibitor, p27Kip1, to cyclin E immunocomplexes, which resulted in a reduction in CDK2 kinase activities and a decrease in levels of endogenous phosphorylated retinoblastoma protein. CDK4 kinase activities were unaffected, as were the levels of the CDK inhibitor p21Cip1 present in cyclin E immunocomplexes. Therefore, overexpression of MMAC1 via adenovirus-mediated gene transfer suppresses tumor cell growth through cell cycle inhibitory mechanisms, and as such, represents a potential therapeutic approach to treating glioblastomas.
 ...
PMID:Adenovirus-mediated gene transfer of MMAC1/PTEN to glioblastoma cells inhibits S phase entry by the recruitment of p27Kip1 into cyclin E/CDK2 complexes. 1034 36

Malignant gliomas frequently show genetic aberrations of genes coding for cell cycle regulatory proteins involved in the control of G1/S phase transition. These include mutation and/or deletion of the retinoblastoma (RB1) gene, homozygous deletion of the CDKN2A and CDKN2B genes, as well as amplification and overexpression of the CDK4 and CDK6 genes. The D-type cyclins (cyclin D1, D2, and D3) promote cell cycle progression from G1 to S phase by binding to and activating the cyclin dependent kinases Cdk4 and Cdk6. Here, we have investigated a series of 110 primary malignant gliomas and 8 glioma cell lines for amplification and expression of the D-type cyclin genes CCND1 (11q13), CCND2 (12p13), and CCND3 (6p21). We found the CCND1 gene amplified and overexpressed in one anaplastic astrocytoma of our tumor series. Two glioblastomas and one anaplastic astrocytoma showed CCND2 gene amplification, but lacked significant overexpression of CCND2 transcripts. Amplification and overexpression of the CCND3 gene was detected in the glioblastoma cell line CCF-STTG1, as well as in one primary glioblastoma and in the sarcomatous component of one gliosarcoma. Our data thus suggest that amplification and increased expression of CCND1 and CCND3 contribute to the loss of cell cycle control in a small fraction of human malignant gliomas.
 ...
PMID:Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. 1041 84

In this study we established the simultaneous status of TP53, p16, p14ARF and PTEN tumor suppressor genes in 34 randomly chosen human glioma cell lines. Nine cell lines (26.4%) harbored mutations or deletions in all four tumor suppressor genes and 22 cell lines (64%) had alterations in at least three. Mutations/deletions were found at the following frequencies: TP53 (76.5%), p14ARF (64.7%), p16 (64.7%), PTEN (73.5%). Thus, there was a high incidence of alterations in the cellular pathways involving the p53 transcription factor (94.1%), the retinoblastoma protein (64.7%) and the PTEN phosphatase (73.5%) and 91% of cell lines carried mutations in two or more pathways. This provides the first clear genetic evidence that these tumor suppressors participate in biological pathways which are functioning separately/independently in glioma cells. The status of the gene alterations did not correlate with tumorigenicity in immunocompromized mice or any clinical parameters. Although the mutation rate was higher in glioma cell lines than that reported for glioma tissues, the alterations were molecularly representative of those found in adult de novo glioblastoma. This study highlights the importance of developing therapeutic approaches applicable to tumors with a broad range of genetic alterations and also provides an invaluable panel of glioma cell lines to make this possible.
 ...
PMID:Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. 1041 87

Gene amplification and enhanced expression of the epidermal growth factor receptor (EGFR) represent the major molecular genetic alteration in glioblastomas and it may play an essential role in cell growth and in the carcinogenic process. On the other hand, the nuclear suppressor proteins PML and p53 are also known to play critical roles in cancer development and in suppressing cell growth. Here we report that, in glioblastoma cells with defective EGFR function, the expressions of both promyelocytic leukaemia (PML) and p53 were altered. Cells that were transfected with the antisense-cDNA of EGFR were found to have more cells in G1 and fewer cells in S phase. In addition, the transfected cells were found to be non-responsive to EGF-induced cell growth. Interestingly, the expression of the suppressors p53 and PML were found to be significantly increased by immunohistochemical assay in the antisense-EGFR cells. Moreover, the PML expression in many of the cells was converted from the nuclear dot pattern into fine-granulated staining pattern. In contrast, the expressions of other cell cycle regulated genes and proto-oncogene, including the cyclin-dependent kinase 4 (cdk4), retinoblastoma, p16INK4a and p21H-ras, were not altered. These data indicate that there are specific inductions of PML and p53 proteins which may account for the increase in G1 and growth arrest in antisense-EGFR treated cells. It also indicates that the EGF, p53 and PML transduction pathways were linked and they may constitute an integral part of an altered growth regulatory programme. The interactions and cross-talks of these critical molecules may be very important in regulating cell growth, differentiation and cellular response to treatment in glioblastomas.
 ...
PMID:Altered expression of the suppressors PML and p53 in glioblastoma cells with the antisense-EGF-receptor. 1057 56


<< Previous 1 2 3 4 5 6 7 8 9 Next >>