Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human L3MBTL1, which contains three malignant brain tumor (MBT) repeats, binds monomethylated and dimethylated lysines, but not trimethylated lysines, in several histone sequence contexts. In crystal structures of L3MBTL1 complexes, the monomethyl- and dimethyllysines insert into a narrow and deep cavity of aromatic residue-lined pocket 2, while a proline ring inserts into shallower pocket 1. We have also engineered a single Y to E substitution within the aromatic cage of the BPTF PHD finger, resulting in a reversal of binding preference from trimethyl- to dimethyllysine in an H3K4 sequence context. In both the "cavity insertion" (L3MBTL1) and "surface groove" (PHD finger) modes of methyllysine recognition, a carboxylate group both hydrogen bonds and ion pairs to the methylammonium proton. Our structural and binding studies of these two modules provide insights into the molecular principles governing the decoding of lysine methylation states, thereby highlighting a methylation state-specific layer of histone mark readout impacting on epigenetic regulation.
Mol Cell 2007 Nov 30
PMID:Structural basis for lower lysine methylation state-specific readout by MBT repeats of L3MBTL1 and an engineered PHD finger. 1804 61

Glioblastoma multiforme (GBM) is an invasive and aggressive primary brain tumor which is associated with a dismal prognosis. We have earlier developed a macroscopic, intracranial, syngeneic GBM model, in which treatment with adenoviral vectors (Ads) expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) plus ganciclovir (GCV) resulted in survival of approximately 20% of the animals. In this model, treatment with Ads expressing Fms-like tyrosine kinase 3 ligand (Flt3L), in combination with Ad-HSV1-TK improves the survival rate to approximately 70% and induces systemic antitumor immunity. We hypothesized that the growth of a large intracranial tumor mass would cause behavioral abnormalities that can be reversed by the combined gene therapy. We assessed the behavior and neuropathology of tumor-bearing animals treated with the combined gene therapy, 3 days after treatment, in long-term survivors, and in a recurrent model of glioma. We demonstrate that the intracranial GBM induces behavioral deficits that are resolved after treatment with Ad-Flt3L/Ad-TK (+GCV). Neuropathological analysis of long-term survivors revealed an overall recovery of normal brain architecture. The lack of long-term behavioral deficits and limited neuropathological abnormalities demonstrate the efficacy and safety of the combined Ad-Flt3L/Ad-TK gene therapy for GBM. These findings can serve to underpin further developments of this therapeutic modality, leading toward implementation of a Phase I clinical trial.
Mol Ther 2008 Apr
PMID:Flt3L in combination with HSV1-TK-mediated gene therapy reverses brain tumor-induced behavioral deficits. 1828 79

Neural stem cells (NSCs) have been identified in the mature central nervous system (CNS), and they reside in specific areas. Cultures of NSCs can be successfully established in vitro by exploiting the NeuroSphere assay. This methodology relies on the continuous exposure of neural cells to mitogens such as epidermal growth factor and fibroblast growth factor-2. Under these conditions, only NSCs and highly undifferentiated progenitors proliferate, whereas committed precursors and terminally differentiated cells are eliminated from the culture. The proper application of this method to the cells allows the establishment of long-term expanding stable NSC lines, starting from different neural tissues as the adult rodent CNS and human brain tumor specimens.
Methods Mol Biol 2008
PMID:Adult neural stem cells. 1836 50

Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. Although considerable progress has been made in surgical and radiation treatment for glioma patients, the impact of these advances on clinical outcome has been disappointing. Therefore, the development of novel therapeutic approaches is essential. Recent reports demonstrate that systemic immunotherapy using dendritic cells (DCs) or peptide vaccines is capable of inducing an antiglioma response. These approaches successfully induce an antitumor immune response and prolong survival in patients with glioma without major side effects. There are several types of glioma, so to achieve effective therapy, it might be necessary to evaluate the molecular genetic abnormalities in individual patient tumors and design novel immunotherapeutic strategies based on the pharmacogenomic findings. Here, we review recent advances in DC- and peptide-based immunotherapy approaches for patients with gliomas.
Trends Mol Med 2008 May
PMID:Cell- and peptide-based immunotherapeutic approaches for glioma. 1840 64

Human brain microvascular endothelial cells (HBMECs) play an essential role as structural and functional components of the blood-brain barrier (BBB). While disruption of the BBB by the brain tumor-secreted matrix metalloproteinase-9 (MMP-9) favors tumor invasion, the role and regulation of MMP-9 secretion by HBMEC themselves in response to carcinogens or brain tumor-derived growth factors has received little attention. Our study delineates a unique brain endothelial phenotype in that MMP-9 secretion is increased upon phorbol 12-myristate 13-acetate (PMA) treatment of HBMEC. Sulforaphane (SFN), an isothiocyanate present in broccoli which exhibits chemopreventive properties, selectively inhibited the secretion of MMP-9 but not that of MMP-2. The decrease in MMP-9 gene expression correlated with a decrease in the expression of the mRNA stabilizing factor HuR protein triggered by SFN. PMA-induced HBMEC migration was also antagonized by SFN. Silencing of the MMP-9 gene inhibited PMA-induced MMP-9 secretion, cell migration, and in vitro tubulogenesis on Matrigel. While SFN inhibited the chemoattractive abilities of brain tumor-derived growth factors, it failed to inhibit PMA-induced tubulogenesis. Our data are indicative of a selective role for SFN to inhibit MMP-9-activated, but not basal, HBMEC migration, and tubulogenesis whose actions could add to SFN's antitumor properties.
Mol Nutr Food Res 2008 Jun
PMID:The diet-derived sulforaphane inhibits matrix metalloproteinase-9-activated human brain microvascular endothelial cell migration and tubulogenesis. 1843 88

Glioblastoma is the most common and severe primary brain tumor in adults. Its aggressive and infiltrative nature renders the current therapeutics of surgical resection, radiation, and chemotherapy relatively ineffective. Accordingly, recent research has focused on the elucidation of various signal transduction pathways in glioblastoma, particularly aberrant activation. This review focuses on the signal transducer and activator of transcription-3 (STAT-3) signal transduction pathway in the context of this devastating tumor. STAT-3 is aberrantly activated in human glioblastoma tissues, and this activation is implicated in controlling critical cellular events thought to be involved in gliomagenesis, such as cell cycle progression, apoptosis, angiogenesis, and immune evasion. There are no reports of gain-of-function mutations in glioblastoma; rather, the activation of STAT-3 is thought to be a consequence of either dysregulation of upstream kinases or loss of endogenous inhibitors. This review provides detailed insight into the multiple mechanisms of STAT-3 activation in glioblastoma, as well as describing endogenous and chemical inhibitors of this pathway and their clinical significance. In glioblastoma, STAT-3 acts a molecular hub to link extracellular signals to transcriptional control of proliferation, cell cycle progression, and immune evasion. Because STAT-3 plays this central role in glioblastoma signal transduction, it has significant potential as a therapeutic target.
Mol Cancer Res 2008 May
PMID:Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. 1850 13

The glutathione S-transferase P1 (GSTP1) is involved in multiple cellular functions, including phase II metabolism, stress response, signaling, and apoptosis. The mechanisms underlying the significantly high GSTP1 expression in many human tumors are, however, currently not well understood. We report here that the GSTP1 gene is a heretofore unrecognized downstream transcriptional target of the tumor suppressor p53. We identified a p53-binding motif comprising two consecutive half-sites located in intron 4 of the GSTP1 gene and is highly homologous to consensus p53-binding motifs in other p53-responsive genes. Using a combination of electrophoretic mobility shift assay and DNase I footprinting analyses, we showed that wild-type p53 protein binds to the GSTP1 p53 motif and luciferase reporter assays showed the motif to be transcriptionally functional in human tumor cells. In a temperature-sensitive p53-mutant cells, levels of both p21/WAF1 and GSTP1 gene transcripts increased time dependently when cells were switched from the inactive mutant state to the wild-type p53 state. Small interfering RNA-mediated reduction of p53 expression resulted in a specific decrease in GSTP1 expression and in tumor cells with mutated p53; adenovirally mediated expression of wild-type p53 increased GSTP1 expression significantly. In a panel of early-passage brain tumor cultures from patients, high levels of GSTP1 transcripts and protein were associated with wild-type p53 and, conversely, low GSTP1 levels with mutant p53. p53 expression knockdown by small interfering RNA increased cisplatin sensitivity. The ability of wild-type p53 to transcriptionally activate the human GSTP1 gene defines a novel mechanism of protecting the genome and, potentially, of tumor drug resistance.
Mol Cancer Res 2008 May
PMID:Identification and functional characterization of the human glutathione S-transferase P1 gene as a novel transcriptional target of the p53 tumor suppressor gene. 1850 28

Human CD133 (human prominin-1), a five transmembrane domain glycoprotein, was originally identified as a cell surface antigen present on CD34+ hematopoietic stem cells. Although the biological function of CD133 is not well understood, antibodies to CD133 epitopes have been widely used to purify hematopoietic stem and progenitor cells. The cancer stem cell (CSC) hypothesis postulates that a rare population of tumor cells possessing increased capacities for self-renewal and tumor initiation is responsible for maintaining the growth of neoplastic tissue. The expression of the CD133 epitopes, AC133 and AC141, has been shown to define a subpopulation of brain tumor cells with significantly increased capacity for tumor initiation in xenograft models. Following the discovery of the AC133/AC141+ population of brain tumor stem cells, the AC133 and AC141 epitopes have been extensively used as markers for purifying CSCs in other solid tumors. There are, however, several issues associated with the use of the AC133 and AC141 CD133 epitopes as markers for CSCs. The antibodies routinely used for purification of AC133 and AC141-positive cells target poorly characterized glycosylated epitopes of uncertain specificity. Discordant expression of the AC133 and AC141 epitopes has been observed, and the epitopes can be absent despite the presence of CD133 protein. In addition, CD133 expression has recently been shown to be modulated by oxygen levels. These factors, in combination with the uncertain biological role of CD133, suggest that the use of CD133 expression as a marker for CSCs should be critically evaluated in each new experimental system and highlight the need for additional CSC surface markers that are directly involved in maintaining CSC properties.
J Mol Med (Berl) 2008 Sep
PMID:The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. 1853 13

Cadherins are cell-to-cell adhesion molecules that play an important role in the establishment of adherent-type junctions by mediating calcium-dependent cellular interactions. The CDH1 gene encodes the transmembrane glycoprotein E-cadherin which is important in maintaining homophilic cell-cell adhesion in epithelial tissues. E-cadherin interacts with catenin proteins to maintain tissue architecture. Structural defects or loss of expression of E-cadherin have been reported as a common feature in several human cancer types. This study aimed to evaluate the expression of E-cadherin and their correlation with clinical features in microdissected brain tumor samples from 81 patients, divided into 62 astrocytic tumors grades I to IV and 19 medulloblastomas, and from 5 white matter non-neoplasic brain tissue samples. E-cadherin (CDH1) gene expression was analyzed by quantitative real-time polymerase chain reaction. Mann-Whitney, Kruskal-Wallis, Kaplan-Meir, and log-rank tests were performed for statistical analyses. We observed a decrease in expression among pathological grades of neuroepithelial tumors. Non-neoplasic brain tissue showed a higher expression level of CDH1 gene than did neuroepithelial tumors. Expression of E-cadherin gene was higher in astrocytic than embryonal tumors (P = 0.0168). Low-grade malignancy astrocytomas (grades I-II) showed higher CDH1 expression than did high-grade malignancy astrocytomas (grades III-IV) and medulloblastomas (P < 0.0001). Non-neoplasic brain tissue showed a higher expression level of CDH1 gene than grade I malignancy astrocytomas, considered as benign tumors (P = 0.0473). These results suggest that a decrease in E-cadherin gene expression level in high-grade neuroepithelial tumors may be a hallmark of malignancy in dedifferentiated tumors and that it may be possibly correlated with their progression and dissemination.
Genet Mol Res 2008 Apr 08
PMID:Differential expression of E-cadherin gene in human neuroepithelial tumors. 1855 95

Molecular targeting agents have become formidable anticancer weapons, which show much promise against the refractory tumors. Functional peptides are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms a basis for potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. Here, we examine growth suppression efficiency of human glioblastomas by dual-peptide targeting. We did simultaneous introduction of two tumor suppressor peptides (p14(ARF) and p16(INK4a) or p16(INK4a) and p21(CIP1) functional peptides) compared with single-peptide introduction using Wr-T-mediated peptide delivery. Wr-T-mediated transport of both p14(ARF) and p16(INK4a) functional peptides (p14-1C and p16-MIS, respectively) into human glioblastoma cell line, U87DeltaEGFR, reversed specific loss of p14 and p16 function, thereby drastically inhibiting tumor growth by >95% within the first 72 h, whereas the growth inhibition was approximately 40% by p14 or p16 single-peptide introduction. Additionally, the combination of p16 and p21(CIP1) (p21-S154A) peptides dramatically suppressed the growth of glioblastoma line Gli36DeltaEGFR, which carries a missense mutation in p53, by >97% after 120 h. Significantly, our murine brain tumor model for dual-peptide delivery showed a substantial average survival enhancement (P < 0.0001) for peptide-treated mice. Wr-T-mediated dual molecular targeting using antitumor peptides is highly effective against growth of aggressive glioblastoma cells in comparison with single molecule targeting. Thus, jointly restoring multiple tumor suppressor functions by Wr-T-peptide delivery represents a powerful approach, with mechanistic implications for development of efficacious molecular targeting therapeutics against intractable human malignancies.
Mol Cancer Ther 2008 Jun
PMID:Potent synergy of dual antitumor peptides for growth suppression of human glioblastoma cell lines. 1856 17


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