CPEB4 knockout mice exhibit normal hippocampus-related synaptic plasticity and memory.

Regulated RNA translation is critical to provide proteins needed to maintain persistent modification of synaptic strength, which underlies the molecular basis of long-term memory (LTM). Cytoplasmic polyadenylation element-binding proteins (CPEBs) are sequence-specific RNA-binding proteins and regulate translation in various tissues. All four CPEBs in vertebrates are expressed in the brain, including the hippocampal neurons, suggesting their potential roles in translation-dependent plasticity and memory.

Identification of novel synergistic targets for rational drug combinations with PI3 kinase inhibitors using siRNA synthetic lethality screening against GBM.

Several small molecules that inhibit the PI3 kinase (PI3K)-Akt signaling pathway are in clinical development. Although many of these molecules have been effective in preclinical models, it remains unclear whether this strategy alone will be sufficient to interrupt the molecular events initiated and maintained by signaling along the pathways because of the activation of other pathways that compensate for the inhibition of the targeted kinase. In this study, we performed a synthetic lethality screen to identify genes or pathways whose inactivation, in combination with the PI3K inhibitors PX-866 and NVPBEZ-235, might result in a lethal phenotype in glioblastoma multiforme (GBM) cells.

NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas.

Aberrant genetic alternations in human gliomas, such as amplification of epidermal growth factor receptor, mutation and/or deletion of tumor suppressor gene PTEN, and mutations of PIK3CA, contribute to constitutive activation of the phosphatidylinositol 3-kinase (PI3K) pathway. We investigated the potential antitumor activity of NVP-BEZ235, which is a novel dual PI3K/mammalian target of rapamycin (mTOR) inhibitor in gliomas. The compound suppressed glioma cell proliferation with IC(50) values in the low nanomolar range by specifically inhibiting the activity of target proteins including Akt, S6K1, S6, and 4EBP1 in the PI3K/Akt/mTOR signaling pathway.

Biomarkers of disease: cerebrospinal fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast cancer, lung cancer and melanoma.

Background: Breast cancer, lung cancer and melanoma metastasize to the meninges in 5-15% of patients. The identification of specific biomarkers of disease may allow for earlier diagnosis and treatment. Preclinical evidence suggests the possible relevance of SDF-1 and VEGF in the homing and neoangiogenesis of metastases.

Phosphorylation of Thr18 and Ser20 of p53 in Ad-p53-induced apoptosis.

The p53 protein plays a critical role in inducing cell cycle arrest or apoptosis. Because p53 is inactivated in human gliomas, restoring p53 function is a major focus of glioma therapy. The most clinically tested strategy for replacing p53 has been adenoviral-mediated p53 gene therapy (Ad-p53).

Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo.

Multiple genetic aberrations in human gliomas contribute to their highly infiltrative and rapid growth characteristics. Focal adhesion kinase (FAK) regulates tumor migration and invasion. Insulin-like growth factor-I receptor (IGF-IR), whose expression correlates with tumor grade, is involved in proliferation and survival.

Proteomic investigation of glioblastoma cell lines treated with wild-type p53 and cytotoxic chemotherapy demonstrates an association between galectin-1 and p53 expression.

Global protein analysis of treated and untreated glioblastoma cell lines was performed. Proteomic analysis revealed the identity of proteins that were significantly modulated by the treatment with wild-type TP53 and the cytotoxic chemotherapy SN38. In particular, galectin-1 was found to be negatively regulated by transfection with TP53 and further down-regulated by SN38.

c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis.

c-Jun, a major transcription factor in the activating protein 1 (AP-1) family of regulatory proteins, is activated by many physiologic and pathologic stimuli. However, whether c-jun is regulated by epigenetic modification of chromatin structure is not clear. We showed here that c-jun was transcriptionally repressed in response to osmotic stress via a truncated HDAC3 generated by caspase-7-dependent cleavage at aspartic acid 391.

Expression of the receptor tyrosine kinase Tie2 in neoplastic glial cells is associated with integrin beta1-dependent adhesion to the extracellular matrix.

The abnormal function of tyrosine kinase receptors is a hallmark of malignant gliomas. Tie2 receptor tyrosine kinase is a specific endothelial cell receptor whose function is positively regulated by angiopoietin 1 (Ang1). Recently, Tie2 has also been found in the nonvascular compartment of several tumors, including leukemia as well as breast, gastric, and thyroid cancers.

A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme.

Background: Laboratory and clinical data suggest that the anti-angiogenic agent, thalidomide, if combined with cytotoxic agents, may be effective against recurrent glioblastoma multiforme (GBM).

Objectives: To determine 6-month progression-free survival (6PFS) and toxicity of temozolomide plus thalidomide in adults with recurrent GBM.

Patients And Methods: Eligible patients had recurrent GBM after surgery, radiotherapy, and/or adjuvant chemotherapy.

Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma.

The phosphatidylinositol 3-kinase pathway is an important regulator of a wide spectrum of tumor-related biological processes, including cell proliferation, survival, and motility, as well as neovascularization. Protein kinase B/Akt is activated in a complex manner through the phosphorylation of protein kinase B/Akt on Thr308 and Ser473. Although protein-dependent kinase-1 has been shown to phosphorylate Akt at Thr308, it is not clear whether there is a distinct kinase that exclusively phosphorylates Akt at Ser473.

The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo.

Accumulating evidence suggests that glutamate plays a key role in the proliferation and invasion of glioblastoma tumors. Astrocytic tumors have been shown to release glutamate at high levels, which may stimulate tumor cell proliferation and motility via activation of glutamate receptors. Excess glutamate has also been found to facilitate tumor invasion by causing excitotoxic damage to normal brain thereby paving a pathway for tumor migration.

Potential efficacy of p16 gene therapy for EBV-positive nasopharyngeal carcinoma.

The p16 cell cycle inhibitory gene is a potentially critical molecular abnormality in nasopharyngeal carcinoma (NPC). Its expression is silenced through either deletion or promoter methylation in the vast majority of NPC. This in turn is associated with absent or reduced protein expression, which has been previously demonstrated by our group to correlate with inferior clinical outcome.

A novel E1A-E1B mutant adenovirus induces glioma regression in vivo.

Malignant gliomas are the most frequently occurring primary brain tumors and are resistant to conventional therapy. Conditionally replicating adenoviruses are a novel strategy in glioma treatment. Clinical trials using E1B mutant adenoviruses have been reported recently and E1A mutant replication-competent adenoviruses are in advanced preclinical testing.

Differential activation of the Fas/CD95 pathway by Ad-p53 in human gliomas.

Adenoviral p53 gene transfer (Ad-p53) induces apoptosis in glioma cells expressing mutant p53, but fails in cells with wild-type p53. Endogenously, gliomas express varied levels of Fas/CD95, yet constitutively high levels of Fas/CD95 ligand. Because the mechanism behind the differential apoptotic response to Ad-p53 infection remains elusive, we examined how the Fas/CD95 pathway is involved in U87MG (wt-p53), D54 (wt-p53), U251MG (mutant-p53), and U373MG (mutant-p53) glioma cell lines.

p16 gene therapy: a potentially efficacious modality for nasopharyngeal carcinoma.

p16 is an important regulator of the cell cycle at the G(1) phase. Frequent aberration of p16 in nasopharyngeal carcinoma (NPC) suggests a role for this tumor suppressor gene in disease development. p16 gene transfer has been demonstrated to be effective in various human cancer models, including breast, lung, and prostate, causing cell cycle arrest, apoptosis, and tumor growth delay.

Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway.

Background: Oncolytic adenoviruses are promising therapies for the treatment of gliomas. However, untargeted viral replication and the paucity of coxsackie-adenovirus receptors (CARs) on tumor cells are major stumbling blocks for adenovirus-based treatment. We studied the antiglioma activity of the tumor-selective Delta-24 adenovirus, which encompasses an early 1 A adenoviral (E1A) deletion in the retinoblastoma (Rb) protein-binding region, and of the Delta-24-RGD adenovirus.

Oncolytic adenoviruses for malignant glioma therapy.

Malignant gliomas are devastating diseases that localize within the central nervous system and are notoriously invasive. Despite recent advances in established treatment modalities such as postoperative radiotherapy and chemotherapy for gliomas, no definitive improvement in survival has been observed. However, progress in the understanding of the biology of these tumors allows for the development of translational research projects and new therapeutic approaches such as gene therapy.

P202, an interferon-inducible protein, inhibits E2F1-mediated apoptosis in prostate cancer cells.

p202, an interferon (IFN) inducible protein, is a phosphonuclear protein involved in the regulation of cell cycle, apoptosis, and differentiation. E2F1 belongs to the E2F family of proteins that are important cell cycle regulators in promoting cell growth. On the other hand, the deregulated expression of E2F1 also triggers apoptosis independent of p53 status.

Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis.

Inactivation of the tumor suppressor gene PTEN and overexpression of VEGF are two of the most common events observed in high-grade malignant gliomas. The purpose of this study was to determine whether PTEN controls VEGF expression in gliomas under normoxic conditions. Transfer of PTEN to human glioma cells resulted in the transduction of a functional PTEN protein as evidenced by the upregulation of p27 and modification of the phosphorylation status of Akt.

MMAC/PTEN tumor suppressor gene regulates vascular endothelial growth factor-mediated angiogenesis in prostate cancer.

Prostate cancer presents with a broad spectrum of biologic behavior, ranging from being an indolent, incidental finding to an aggressively invasive and metastatic disease. An improved understanding of the events involved in prostate cancer progression is critically important to its diagnosis and staging, as well as to the development of new therapies. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of an angiogenic, gene-driven switch.

Inhibition of prostate tumor angiogenesis by the tumor suppressor CEACAM1.

We have previously shown that CEACAM1, a cell-adhesion molecule, acts as a tumor suppressor in prostate carcinoma. Expression of CEACAM1 in prostate cancer cells suppresses their growth in vivo. However, CEACAM1 has no effect on the growth of prostate cancer cells in vitro.

MBP-1 mediated apoptosis involves cytochrome c release from mitochondria.

MBP-1, a cellular factor, appears to be involved in multiple functions, including transcriptional modulation, apoptosis and cell growth regulation. In this study, we have investigated the signaling pathway involved in MBP-1 mediated apoptotic cell death. Human carcinoma cells infected with a replication deficient adenovirus expressing MBP-1 (AdMBP-1) induced apoptosis, when compared with cells infected by replication-defective adenovirus (dl312) as a negative control.

Promoter analysis of tumor suppressor gene PTEN: identification of minimum promoter region.

Mutations of PTEN, a tumor suppressor gene located on chromosome 10, which encodes a protein-tyrosine and lipid-phosphatase, are prevalent in various human cancers, including glioblastoma. Despite extensive characterization of PTEN mutations in human cancers and a relatively good understanding of the molecular roles of PTEN in the control of cellular processes, little is known about modes of PTEN regulation. To understand the regulation of expression of the tumor suppressor gene PTEN, we isolated a 2212 bp fragment from the human BAC clone 46B12 DNA.

Apoptosis induced by adenovirus-mediated p53 gene transfer in human glioma correlates with site-specific phosphorylation.

Therapeutic replacement of the p53 gene using an adenovirus vector (Ad-p53) may be an effective alternative to conventional therapies for the treatment of glioma. We have previously demonstrated that the introduction of Ad-p53 into glioma cells containing mutant p53 induces apoptosis, whereas glioma cells containing wild-type p53 are resistant. However, Ad-p53 will enhance the radiosensitivity of wild-type p53 glioma cells by increasing their tendency for apoptosis.