Search results for "Oncogene"
showing 10 items of 1005 documents
Suppression of ischemia-induced fos expression and AP-1 activity by an antisense oligodeoxynucleotide to c-fos mRNA.
1994
The molecular events of brain adaptation to injury that may underlie functional recovery after stroke remain largely undefined. Recent observations of altered gene expression in ischemic brain using animal stroke models have opened new avenues for exploration of the biochemical cascades after stroke [1–11]. These postischemic events include an increase in extracellular excitatory amino acid neurotransmitters such as glutamate. Glutamate receptor–mediated activation of phospholipases and protein kinases results in the alteration of nuclear regulatory processes, including the expression of immediate early genes such as c-fos, junB, and c-jun [5, 12]. The Fos, Jun, and JunB proteins have been …
Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine
2006
Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumours (malignant gliomas). The mechanism of TMZ-induced glioma cell death is unknown. Here, we show that malignant glioma cells undergo apoptosis following treatment with the methylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and TMZ. Cell death determined by colony formation and apoptosis following methylation is greatly stimulated by p53. Transfection experiments with O(6)-methylguanine-DNA methyltransferase (MGMT) and depletion of MGMT by O(6)-benzylguanine showed that, in gliomas, the apoptotic signal originates from O(6)-methylguanine (O(6)MeG) and that repair of O(6)MeG by MGMT prevent…
Apoptosis induced by MNNG in human TK6 lymphoblastoid cells is p53 and Fas/CD95/Apo-1 related.
2003
Agents inducing O(6)-methylguanine (O(6)MeG) in DNA, such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), are not only highly mutagenic and carcinogenic but also cytotoxic because of the induction of apoptosis. In CHO fibroblasts, apoptosis triggered by O(6)MeG requires cell proliferation and MutSalpha-dependent mismatch repair and is related to the induction of DNA double-strand breaks (DSBs). Furthermore, it is mediated by Bcl-2 degradation and does not require p53 for which the cells were mutated [Cancer Res. 60 (2000) 5815]. Here we studied cytotoxicity and apoptosis induced by MNNG in a pair of human lymphoblastoid cells expressing wild-type p53 (TK6) and mutant p53 (WTK1) and show tha…
Cloning and functional analysis of cDNA encoding the hamster Bcl-2 protein.
2000
We have cloned cDNA encoding hamster Bcl-2 protein from total RNA of CHO-9 cells by RT-PCR using oligonucleotide primers sharing homology with the sequence of mouse and rat bcl-2. The fragments spanning the total coding region were cloned into pCR4-TOPO and sequenced for verification. The hamster bcl-2 cDNA has a size of 711 nucleotides and encodes a polypeptide of 236 amino acids. Hamster Bcl-2 shares 95.8 and 88.6% similarity with mouse and human Bcl-2, respectively. Northern blot analysis revealed a single 7.5 kb bcl-2 transcript in hamster (CHO-9), mouse (BK4), and rat (H5) cells and a 8.5 kb bcl-2 mRNA in human (HeLa MR) cells. The bcl-2 cDNA (771 bp) was recloned into pcDNA3 and the r…
PTEN Deletion in Adult Mice Induces Hypoinsulinemia With Concomitant Low Glucose Levels
2022
The PI3K/AKT pathway, negatively regulated by PTEN, plays a paramount role in glucose metabolism regulation due to its activation by the insulin receptor signaling pathway. We generated a PTEN-KO mouse to evaluate the systemic effect of the overactivation of the PI3K/AKT pathway in insulin signaling and glucose homeostasis. Our results demonstrate that PTEN-KO mice show very low glucose levels in the fasted state, which poorly respond to glucose and pyruvate administration. Insulinemia decreased without alterations in pancreatic islets. Among the possible reasons, we uncover the deregulation of the expression of proximal tubule glucose transporter and consequent glycosuria. Moreover, we evi…
QSAR of Natural Sesquiterpene Lactones as Inhibitors of Myb-dependent Gene Expression
2017
Background Protein c-Myb is a therapeutic target. Some sesquiterpene lactones suppress Myb-dependent gene expression, which results in their potential anti-cancer activity. Material & methods Database ChEMBL is a representative of lactones for physicochemical and physiochemical properties. Data presented for 31 natural lactones are discussed in terms of quantitative structureactivity relationships with the objective to predict inhibitors of Myb-induced gene expression. Several constitutional descriptors are related to structure-activity. α-Methylene-γ-lactone groups enhance while OH functions worsen potency. The latter feature is in agreement with the fact that the more lipophilic the lacto…
Histone deacetylase A key enzyme for the binding of regulatory proteins to chromatin
1993
AbstractCore histones can be modified by reversible, posttranslational acetylation of specific lysine residues within the N-terminal protein domains. The dynamic equilibrium of acetylation is maintained by two enzyme activities, histone acetyltransferase and histone deacetylase. Recent data on histone deacetylases and on anionic motifs in chromatin- or DNA-binding regulatory proteins (e.g. transcription factors, nuclear proto-oncogenes) are summarized and united into a hypothesis which attributes a key function to histone deacetylation for the binding of regulatory proteins to chromatin by a transient, specific local increase of the positive charge in the N-terminal domains of nucleosomal c…
Conformational control of Bax localization and apoptotic activity by Pro168.
2004
In healthy cells, Bax resides inactive in the cytosol because its COOH-terminal transmembrane region (TMB) is tucked into a hydrophobic pocket. During apoptosis, Bax undergoes a conformational change involving NH2-terminal exposure and translocates to mitochondria to release apoptogenic factors. How this process is regulated remains unknown. We show that the TMB of Bax is both necessary and sufficient for mitochondrial targeting. However, its availability for targeting depends on Pro168 located within the preceding loop region. Pro168 mutants of Bax lack apoptotic activity, cannot rescue the apoptosis-resistant phenotype of Bax/Bak double knockout cells, and are retained in the cytosol even…
A new evolutionary paradigm for the Parkinson disease gene DJ-1.
2006
The DJ-1 gene is extensively studied because of its involvement in familial Parkinson disease. DJ-1 belongs to a complex superfamily of genes that includes both prokaryotic and eukaryotic representatives. We determine that many prokaryotic groups, such as proteobacteria, cyanobacteria, spirochaetes, firmicutes, or fusobacteria, have genes, often incorrectly called "Thij," that are very close relatives of DJ-1, to the point that they cannot be clearly separated from the eukaryotic DJ-1 genes by phylogenetic analyses of their sequences. In addition, and contrary to a previous study that suggested that DJ-1 genes were animal specific, we show that DJ-1 genes are found in at least 5 of the 6 ma…
Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML).
2004
Fms-like tyrosine kinase 3 (FLT3) receptor mutations as internal tandem duplication (ITD) or within the kinase domain are detected in up to 35% of patients with acute myeloid leukemia (AML). N-benzoyl staurosporine (PKC412), a highly effective inhibitor of mutated FLT3 receptors, has significant antileukemic efficacy in patients with FLT3-mutated AML. Mutation screening of FLT3 exon 20 in AML patients (n = 110) revealed 2 patients with a novel mutation (Y842C) within the highly conserved activation loop of FLT3. FLT3-Y842C-transfected 32D cells showed constitutive FLT3 tyrosine phosphorylation and interleukin 3 (IL-3)-independent growth. Treatment with PKC412 led to inhibition of proliferat…