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1.
Nat Chem ; 10(10): 1008-1015, 2018 10.
Article in English | MEDLINE | ID: mdl-30150725

ABSTRACT

Alloying provides a means by which to tune a metal catalyst's electronic structure and thus tailor its performance; however, mean-field behaviour in metals imposes limits. To access unprecedented catalytic behaviour, materials must exhibit emergent properties that are not simply interpolations of the constituent components' properties. Here we show an emergent electronic structure in single-atom alloys, whereby weak wavefunction mixing between minority and majority elements results in a free-atom-like electronic structure on the minority element. This unusual electronic structure alters the minority element's adsorption properties such that the bonding with adsorbates resembles the bonding in molecular metal complexes. We demonstrate this phenomenon with AgCu alloys, dilute in Cu, where the Cu d states are nearly unperturbed from their free-atom state. In situ electron spectroscopy demonstrates that this unusual electronic structure persists in reaction conditions and exhibits a 0.1 eV smaller activation barrier than bulk Cu in methanol reforming. Theory predicts that several other dilute alloys exhibit this phenomenon, which offers a design approach that may lead to alloys with unprecedented catalytic properties.

2.
Mol Neurobiol ; 55(10): 8124-8153, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29508283

ABSTRACT

The NH2tau 26-44 aa (i.e., NH2htau) is the minimal biologically active moiety of longer 20-22-kDa NH2-truncated form of human tau-a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)-which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated. We explored the in vivo effects evoked by subchronic intracerebroventricular (i.c.v.) infusion of NH2htau or its reverse counterpart into two lines of young (2-month-old) wild-type mice (C57BL/6 and B6SJL). Six days after its accumulation into hippocampal parenchyma, significant impairment in memory/learning performance was detected in NH2htau-treated group in association with reduced synaptic connectivity and neuroinflammatory response. Compromised short-term plasticity in paired-pulse facilitation paradigm (PPF) was detected in the CA3/CA1 synapses from NH2htau-impaired animals along with downregulation in calcineurin (CaN)-stimulated pCREB/c-Fos pathway(s). Importantly, these behavioral, synaptotoxic, and neuropathological effects were independent from the genetic background, occurred prior to frank neuronal loss, and were specific because no alterations were detected in the control group infused with its reverse counterpart. Finally, a 2.0-kDa peptide which biochemically and immunologically resembles the injected NH2htau was endogenously detected in vivo, being present in hippocampal synaptosomal preparations from AD subjects. Given that the identification of the neurotoxic tau species is mandatory to develop a more effective tau-based immunological approach, our evidence can have important translational implications for cure of human tauopathies.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Immunotherapy , tau Proteins/chemistry , tau Proteins/metabolism , Alzheimer Disease/complications , Alzheimer Disease/physiopathology , Animals , Behavior, Animal , Cognition , Cyclic AMP Response Element-Binding Protein/metabolism , Gliosis/complications , Gliosis/pathology , Gliosis/physiopathology , Hippocampus/pathology , Hippocampus/physiopathology , Humans , Inflammation/pathology , Male , Memory , Memory Consolidation , Mice, Inbred C57BL , Neuronal Plasticity , Neuropathology , Neurotransmitter Agents/metabolism , Peptides/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Solubility , Synapses/metabolism , Synaptosomes/metabolism , Task Performance and Analysis
3.
Phys Chem Chem Phys ; 18(4): 2292-6, 2016 Jan 28.
Article in English | MEDLINE | ID: mdl-26700139

ABSTRACT

Iridium oxide based electrodes are among the most promising candidates for electrocatalyzing the oxygen evolution reaction, making it imperative to understand their chemical/electronic structure. However, the complexity of iridium oxide's electronic structure makes it particularly difficult to experimentally determine the chemical state of the active surface species. To achieve an accurate understanding of the electronic structure of iridium oxide surfaces, we have combined synchrotron-based X-ray photoemission and absorption spectroscopies with ab initio calculations. Our investigation reveals a pre-edge feature in the O K-edge of highly catalytically active X-ray amorphous iridium oxides that we have identified as O 2p hole states forming in conjunction with Ir(III). These electronic defects in the near-surface region of the anionic and cationic framework are likely critical for the enhanced activity of amorphous iridium oxides relative to their crystalline counterparts.

4.
Transl Psychiatry ; 4: e417, 2014 Jul 29.
Article in English | MEDLINE | ID: mdl-25072322

ABSTRACT

D-aspartate (D-Asp) is an atypical amino acid, which is especially abundant in the developing mammalian brain, and can bind to and activate N-methyl-D-Aspartate receptors (NMDARs). In line with its pharmacological features, we find that mice chronically treated with D-Asp show enhanced NMDAR-mediated miniature excitatory postsynaptic currents and basal cerebral blood volume in fronto-hippocampal areas. In addition, we show that both chronic administration of D-Asp and deletion of the gene coding for the catabolic enzyme D-aspartate oxidase (DDO) trigger plastic modifications of neuronal cytoarchitecture in the prefrontal cortex and CA1 subfield of the hippocampus and promote a cytochalasin D-sensitive form of synaptic plasticity in adult mouse brains. To translate these findings in humans and consistent with the experiments using Ddo gene targeting in animals, we performed a hierarchical stepwise translational genetic approach. Specifically, we investigated the association of variation in the gene coding for DDO with complex human prefrontal phenotypes. We demonstrate that genetic variation predicting reduced expression of DDO in postmortem human prefrontal cortex is mapped on greater prefrontal gray matter and activity during working memory as measured with MRI. In conclusion our results identify novel NMDAR-dependent effects of D-Asp on plasticity and physiology in rodents, which also map to prefrontal phenotypes in humans.


Subject(s)
Brain/physiology , D-Aspartic Acid/physiology , Gray Matter/physiology , Neuronal Plasticity/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Adult , Animals , Brain/pathology , D-Aspartate Oxidase/genetics , D-Aspartate Oxidase/physiology , Female , Gene Deletion , Gene Expression Regulation, Enzymologic/genetics , Gray Matter/pathology , Hippocampus/pathology , Hippocampus/physiology , Humans , Magnetic Resonance Imaging , Male , Memory, Short-Term/physiology , Mice , Mice, Inbred C57BL , Neuronal Plasticity/genetics , Organ Size/genetics , Organ Size/physiology , Phenotype , Polymorphism, Single Nucleotide/genetics , Prefrontal Cortex/pathology , Prefrontal Cortex/physiology , Protein Biosynthesis/genetics , RNA, Messenger/genetics
5.
Cell Death Differ ; 20(8): 1017-30, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23538417

ABSTRACT

ProNGF, the precursor of mature nerve growth factor (NGF), is the most abundant form of NGF in the brain. ProNGF and mature NGF differ significantly in their receptor interaction properties and in their bioactivity. ProNGF increases markedly in the cortex of Alzheimer's disease (AD) brains and proNGF\NGF imbalance has been postulated to play a role in neurodegeneration. However, a direct proof for a causal link between increased proNGF and AD neurodegeneration is lacking. In order to evaluate the consequences of increased levels of proNGF in the postnatal brain, transgenic mice expressing a furin cleavage-resistant form of proNGF, under the control of the neuron-specific mouse Thy1.2 promoter, were derived and characterized. Different transgenic lines displayed a phenotypic gradient of neurodegenerative severity features. We focused the analysis on the two lines TgproNGF#3 and TgproNGF#72, which shared learning and memory impairments in behavioral tests, cholinergic deficit and increased Aß-peptide immunoreactivity. In addition, TgproNGF#3 mice developed Aß oligomer immunoreactivity, as well as late diffuse astrocytosis. Both TgproNGF lines also display electrophysiological alterations related to spontaneous epileptic-like events. The results provide direct evidence that alterations in the proNGF/NGF balance in the adult brain can be an upstream driver of neurodegeneration, contributing to a circular loop linking alterations of proNGF/NGF equilibrium to excitatory/inhibitory synaptic imbalance and amyloid precursor protein (APP) dysmetabolism.


Subject(s)
Epilepsy/physiopathology , Homeostasis/physiology , Learning Disabilities/physiopathology , Memory Disorders/physiopathology , Nerve Growth Factor/physiology , Neurodegenerative Diseases/physiopathology , Protein Precursors/physiology , Aging/physiology , Animals , Behavior, Animal/physiology , Disease Models, Animal , Hippocampus/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Growth Factor/deficiency , Nerve Growth Factor/genetics , Phenotype , Protein Precursors/deficiency , Protein Precursors/genetics
6.
J Biol Regul Homeost Agents ; 27(2 Suppl): 37-47, 2013.
Article in English | MEDLINE | ID: mdl-24813314

ABSTRACT

The discovery of long-term potentiation (LTP) of hippocampal synaptic transmission, which represents a classical model for learning and memory at the cellular level, has stimulated over the past years substantial progress in the understanding of pathogenic mechanisms underlying cognitive disorders, such as Alzheimer’s disease (AD). Multiple lines of evidence indicate synaptic dysfunction not only as a core feature but also a leading cause of AD. Multiple pathways may play a significant role in the execution of synaptic dysfunction and neuronal death triggered by beta-amyloid (Abeta) in AD. Following intensive investigations into LTP in AD models, a variety of compounds have been found to rescue LTP impairment via numerous molecular mechanisms. Yet very few of these findings have been successfully translated into disease-modifying compounds in humans. This review recapitulates the emerging disease-modifying strategies utilized to modulate hippocampal synaptic plasticity with particular attention to approaches targeting ligand-gated ion channels, G-protein-coupled receptors (GPCRs), Receptor Tyrosine Kinases (RTKs) and epigenetic mechanisms. It is hoped that novel multi-targeted drugs capable of regulating spine plasticity might be effective to counteract the progression of AD and related cognitive syndromes.

7.
J Neuroimmunol ; 224(1-2): 85-92, 2010 Jul 27.
Article in English | MEDLINE | ID: mdl-20570369

ABSTRACT

We characterized the role of adenosine receptor (AR) subtypes in the modulation of glutamatergic neurotransmission by the chemokine fractalkine (CX3CL1) in mouse hippocampal CA1 neurons. CX(3)CL1 causes a reversible depression of excitatory postsynaptic current (EPSC), which is abolished by the A(3)R antagonist MRS1523, but not by A(1)R (DPCPX) or A(2A)R (SCH58261) antagonists. Consistently, CX3CL1-induced EPSC depression is absent in slices from A(3)R(-/-) but not A(1)R(-/-) or A(2A)R(-/-) mice. Further, A(3)R stimulation causes similar EPSC depression. In cultured neurons, CX3CL1-induced depression of AMPA current shows A(1)R-A(3)R pharmacology. We conclude that glutamatergic depression induced by released adenosine requires the stimulation of different ARs.


Subject(s)
CA1 Region, Hippocampal/immunology , CA1 Region, Hippocampal/metabolism , Chemokine CX3CL1/physiology , Excitatory Postsynaptic Potentials/immunology , Neural Inhibition/immunology , Receptors, Purinergic P1/physiology , Synaptic Transmission/immunology , Adenosine A1 Receptor Antagonists , Adenosine A2 Receptor Antagonists , Adenosine A3 Receptor Antagonists , Animals , CA1 Region, Hippocampal/ultrastructure , Cells, Cultured , Excitatory Postsynaptic Potentials/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Neural Inhibition/genetics , Organ Culture Techniques , Patch-Clamp Techniques , Presynaptic Terminals/immunology , Presynaptic Terminals/metabolism , Receptor, Adenosine A1/deficiency , Receptor, Adenosine A1/physiology , Receptor, Adenosine A3/deficiency , Receptor, Adenosine A3/physiology , Receptors, Adenosine A2/deficiency , Receptors, Adenosine A2/physiology , Receptors, Purinergic P1/deficiency , Receptors, Purinergic P1/genetics , Synaptic Transmission/genetics
8.
J Neurophysiol ; 95(5): 3105-12, 2006 May.
Article in English | MEDLINE | ID: mdl-16467425

ABSTRACT

Synchronous neuronal firing can be induced in hippocampal slices in the absence of synaptic transmission by lowering extracellular Ca2+ and raising extracellular K+. However, the ionic mechanisms underlying this nonsynaptic synchronous firing are not well understood. In this study we have investigated the role of KCNQ/Kv7 channels in regulating this form of nonsynaptic bursting activity. Incubation of rat hippocampal slices in reduced (<0.2 mM) [Ca2+]o and increased (6.3 mM) [K+]o, blocked synaptic transmission, increased neuronal firing, and led to the development of spontaneous periodic nonsynaptic epileptiform activity. This activity was recorded extracellularly as large (4.7 +/- 1.9 mV) depolarizing envelopes with superimposed high-frequency synchronous population spikes. These intraburst population spikes initially occurred at a high frequency (about 120 Hz), which decayed throughout the burst stabilizing in the gamma-frequency band (30-80 Hz). Further increasing [K+]o resulted in an increase in the interburst frequency without altering the intraburst population spike frequency. Application of retigabine (10 microM), a Kv7 channel modulator, completely abolished the bursts, in an XE-991-sensitive manner. Furthermore, application of the Kv7 channel blockers, linopirdine (10 microM) or XE-991 (10 microM) alone, abolished the gamma frequency, but not the higher-frequency population spike firing observed during low Ca2+/high K+ bursts. These data suggest that Kv7 channels are likely to play a role in the regulation of synchronous population firing activity.


Subject(s)
Action Potentials/physiology , Hippocampus/cytology , KCNQ Potassium Channels/physiology , Neurons/physiology , Periodicity , Synaptic Transmission/physiology , Action Potentials/drug effects , Action Potentials/radiation effects , Animals , Anthracenes/pharmacology , Calcium/metabolism , Carbamates/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Electric Stimulation/methods , Hippocampus/physiology , In Vitro Techniques , Indoles/pharmacology , Male , Neurons/drug effects , Neurons/radiation effects , Phenylenediamines/pharmacology , Potassium/metabolism , Potassium/pharmacology , Potassium Channel Blockers/pharmacology , Pyridines/pharmacology , Rats
9.
Cell Death Differ ; 13(2): 335-45, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16096654

ABSTRACT

Twist is a member of the basic helix-loop-helix family of transcription factors. An aberrant Twist expression has been found in diverse types of cancer, including sarcomas, carcinomas and lymphomas, supporting a role for Twist in tumor progression. Twist is known to be essential for mesodermal development. However, since a prolonged Twist expression results in a block of muscle, cartilage and bone differentiation, Twist has to be excluded from somites during late embryogenesis for terminal differentiation to occur. This implies that Twist expression must be target of a tight control. Here we provide evidence that Twist undergoes post-transcriptional regulation. Twist is substrate for cleavage by caspases during apoptosis and its cleavage results in ubiquitin-mediated proteasome degradation. Our findings suggest that Twist post-transcriptional regulation may play an important role in tissue determination and raise the possibility that alterations in the protein turnover may account for Twist overexpression observed in tumors.


Subject(s)
Apoptosis , Caspase 1/metabolism , Proteasome Endopeptidase Complex/metabolism , Twist-Related Protein 1/metabolism , Animals , Blotting, Northern , Caspase 1/chemistry , Caspase 1/genetics , Cell Differentiation/physiology , Cell Line, Tumor , Cells, Cultured , Disease Progression , Gene Expression Regulation , Humans , Mice , Mice, Inbred BALB C , Proteasome Endopeptidase Complex/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , Twist-Related Protein 1/chemistry , Twist-Related Protein 1/genetics , Ubiquitin/metabolism
10.
Chemphyschem ; 6(9): 1727-30, 2005 Sep 05.
Article in English | MEDLINE | ID: mdl-16144008
11.
J Pathol ; 190(5): 531-6, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10727978

ABSTRACT

Atypical lipomatous tumours (ALTs) represent a distinctive subset of mesenchymal neoplasms featuring mature adipocytic differentiation. Most ALTs are characterized cytogenetically by the presence of supernumerary ring and/or long marker chromosomes derived from the chromosomal region 12q13-15. The 12q13-15 chromosome region contains several genes which may play an important role in human tumorigenesis. A series of ALTs was analysed by investigating the MDM2, CDK4, and HMGI-C genes and their proteins. The study was extended to a series of ordinary lipomas, to determine whether the immunohistochemical investigation of these gene products might play any diagnostic role. Cytogenetic analysis revealed the presence of various cytogenetic aberrations involving the 12q13-15 region in 11/18 (61%) lipomas and of ring chromosomes in all ALTs. Overexpression of mdm2 protein was observed in 6/12 (50%) atypical lipomatous tumours. All lipomas were mdm2-negative. cdk4 overexpression was present in 100% of ALTs. Weak cdk4 immunopositivity was detected in 2/18 (11%) ordinary lipomas in a minority of cells. HMGI-C immunopositivity was observed in 10/12 (83%) ALTs. Positive immunoreactivity was also observed in 8/18 (44%) lipomas. Southern blot analysis revealed amplification of the CDK4 and MDM2 genes in 3/5 ALTs analysed. HMGI-C was amplified in 3/5 cases and was deleted in one case. Mutation analysis of the CDK4 gene did not demonstrate any mutation. These data support the hypothesis that ordinary lipomas may form a molecular genetic and morphological continuum with ALT. At one end of the spectrum are lipomas characterized by 12q13-15 rearrangements and HMGI-C activation and at the other end are ALTs with ring chromosomes, 12q13-15 amplification with overrepresentation of the HMGI-C, CDK4 or MDM2 genes, and aberrant cdk4, mdm2, and HMGI-C protein expression. These findings not only provide insights into the molecular pathogenesis of lipomatous tumours, but also indicate that the immunohistochemical analysis of mdm2 and cdk4 may help to increase diagnostic accuracy.


Subject(s)
Liposarcoma/genetics , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Soft Tissue Neoplasms/genetics , Adult , Aged , Blotting, Southern , Chromosomes, Human, Pair 12 , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinases/genetics , Cyclin-Dependent Kinases/metabolism , Female , Follow-Up Studies , Gene Expression , HMGA2 Protein , High Mobility Group Proteins/genetics , High Mobility Group Proteins/metabolism , Humans , Immunoenzyme Techniques , Lipoma/genetics , Lipoma/metabolism , Liposarcoma/metabolism , Male , Middle Aged , Neoplasm Proteins/metabolism , Nuclear Proteins/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-mdm2 , Soft Tissue Neoplasms/metabolism
12.
Int J Cancer ; 84(4): 432-6, 1999 Aug 20.
Article in English | MEDLINE | ID: mdl-10404099

ABSTRACT

Frequent loss of a specific chromosomic region in cancers is often associated with inactivation of a tumor-suppressor gene. The long arm of chromosome 10 is deleted in several types of tumor, among them squamous-cell carcinomas of the head and neck (HNSCC). To determine the role of 10q deletions in the tumorigenesis of the upper respiratory tract, 47 HNSCCs were examined for loss of heterozygosity (LOH) at 10q: 43% of the cases analyzed showed LOH at 10q, and 2 distinct hot spots of deletion were identified, at 10q22-23 and 10q25-26. The possible involvement of pTEN/MMAC1, a tumor-suppressor gene mapped at 10q23, was also evaluated. No mutation, homozygous deletion or loss of expression of pTEN/MMAC1 was detected, indicating that inactivation of this gene plays a minor role in HNSCC development. Interestingly, the frequency of deletion at 10q was greater in invasive carcinoma than in adjacent carcinoma in situ, and a significant association between LOH and poor prognosis was observed. Taken together, our results suggest the presence in the long arm of chromosome 10 of (a) tumor-suppressor gene(s) other than pTEN/MMAC1 and presumably involved in the malignant progression of tumors of the upper respiratory tract. Int. J. Cancer (Pred. Oncol.) 84:432-436, 1999.


Subject(s)
Carcinoma, Squamous Cell/genetics , Chromosomes, Human, Pair 10 , Head and Neck Neoplasms/genetics , Loss of Heterozygosity , Polymorphism, Single-Stranded Conformational , Respiratory Tract Neoplasms/genetics , Blotting, Southern/methods , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/surgery , Chromosome Mapping , Genetic Markers , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/surgery , Humans , Mucous Membrane/pathology , Polymerase Chain Reaction/methods , Predictive Value of Tests , Prognosis , Respiratory Tract Neoplasms/mortality , Respiratory Tract Neoplasms/pathology , Respiratory Tract Neoplasms/surgery , Survival Analysis , Time Factors
13.
Br J Cancer ; 78(9): 1147-51, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9820170

ABSTRACT

Patients affected by squamous cell carcinoma of the head and neck (HNSCC) show frequent occurrence of multiple cancers and widespread precancerous lesions in the mucosa of the upper respiratory tract, a phenomenon known as field cancerization. In this study, we investigated the role of genetic instability in the development of HNSCC and in particular in tumour multiplicity phenomena of the upper respiratory tract. For this purpose, we analysed microsatellite instability (MI) and loss of heterozygosity (LOH) at 20 loci mapping on five chromosomal arms in 67 HNSCC patients, 45 of whom had a single cancer and 22 had multiple primary tumours. The possible involvement of the hMLH1 gene in genetic instability and as a potential target of 3p21 deletion phenomena in head and neck cancers was also investigated. Our data indicate that mismatch repair-related genetic instability plays a minor role in the carcinogenesis of HNSCC and in tumour multiplicity of the head and neck region. Moreover, our results exclude a role for the hMLH1 gene as a determinant of MI and as a specific gene target of deletion at 3p21 in HNSCC. We conclude that presumably other genetic mechanisms, such as those hypothesized for MI-negative hereditary non-polyposis colorectal cancer patients, may play a major role in the carcinogenesis of the mucosa of the upper respiratory tract.


Subject(s)
Carcinoma, Squamous Cell/genetics , Head and Neck Neoplasms/genetics , Microsatellite Repeats , Alleles , Carcinoma, Squamous Cell/pathology , Chromosomes, Human, Pair 3 , DNA, Neoplasm/genetics , Female , Head and Neck Neoplasms/pathology , Humans , Loss of Heterozygosity , Male , Middle Aged , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/pathology
14.
Am J Pathol ; 151(6): 1531-9, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9403703

ABSTRACT

Myxoid and round cell liposarcoma represents a morphological spectrum in which tumor progression from low-grade myxoid to high-grade round cell areas is frequently observed. A distinctive t(12;16)(q13;p11) reciprocal translocation rearranges the CHOP gene localized to 12q13 in most cases. Data concerning the occurrence of cell cycle aberrations in this subset of mesenchymal malignancies are very limited. Therefore, we analyzed a histologically homogeneous series of 21 cases of myxoid and round cell liposarcoma. The p53 pathway was studied by investigating the TP53 gene and protein, mdm2 protein, and p21Waf1 protein. The Rb-cyclin D pathway was analyzed by studying the pRb protein, the p16MTS1 gene, cyclin D1, cyclin D3, p27Kip1, cdk4, and cdk6 proteins. In contrast with the rare involvement of the TP53 gene in well differentiated liposarcoma, aberrations of the TP53 gene were observed in approximately 30% of cases of myxoid and round cell liposarcoma. Notably, mdm2 overexpression was seen in 56% of cases and correlated with histological grade, therefore indicating a possible role in tumor progression. Abnormalities involving the Rb-cyclin D pathway were observed in more than 90% of cases. pRb loss was present in one-third of cases and, at variance with that observed in other subsets of sarcoma, overexpression of cyclin Ds represented a rare event. Interestingly, upregulation of either cdk4 or cdk6 was demonstrated in 85% of cases.


Subject(s)
Chromosome Aberrations , G1 Phase/genetics , Liposarcoma, Myxoid/genetics , Cyclin D , Cyclins/genetics , Cyclins/metabolism , DNA Primers/chemistry , DNA, Neoplasm/analysis , Disease Progression , Humans , Immunohistochemistry , Liposarcoma/genetics , Liposarcoma/metabolism , Liposarcoma/pathology , Liposarcoma, Myxoid/metabolism , Liposarcoma, Myxoid/pathology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Point Mutation , Polymorphism, Single-Stranded Conformational , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
15.
Cancer Res ; 57(12): 2366-8, 1997 Jun 15.
Article in English | MEDLINE | ID: mdl-9192810

ABSTRACT

The deregulation of several cell cycle-related genes participates in neoplastic transformation. Cell cycle progression is driven by cyclin-dependent kinases, which are positively regulated by association with cyclins and negatively regulated by binding to inhibitory subunits. The activity of cyclin-dependent kinases is also regulated by the phosphorylation status, which is controlled by the antagonistic action of wee1 kinase and CDC25 phosphatases. Three CDC25 genes are present in human cells: CDC25A, CDC25B, and CDC25C. These three genes function at different phases of the cell cycle. Whereas CDC25A and CDC25B are expressed throughout the cell cycle, with peak expression in G1 for CDC25A and in both G1-S-phase and G2 for CDC25B, CDC25C is predominantly expressed in G2. Several lines of evidence suggest a role for CDC25s as oncogenes. CDC25A and CDC25B cooperate with Ha-ras or loss of Rb1 in the oncogenic transformation of rodent fibroblasts. Moreover, they are transcriptional targets of c-myc, and CDC25A in particular plays an important role as a mediator of myc functions. On the basis of the evidence that CDC25 phosphatases can act as oncogenes, we analyzed the expression of CDC25A, CDC25B, and CDC25C genes in 20 squamous cell carcinomas of the head and neck by quantitative reverse transcription-PCR. Our results show that whereas CDC25C is expressed at a low level with no relevant differences between neoplastic tissue and normal mucosa, CDC25A and CDC25B are overexpressed in a large fraction of tumors.


Subject(s)
Cell Cycle Proteins/metabolism , Phosphoprotein Phosphatases/metabolism , Protein Tyrosine Phosphatases/metabolism , cdc25 Phosphatases , Carcinoma, Squamous Cell/metabolism , Head and Neck Neoplasms/metabolism , Humans , Polymerase Chain Reaction
16.
Blood ; 89(7): 2523-8, 1997 Apr 01.
Article in English | MEDLINE | ID: mdl-9116298

ABSTRACT

A large fraction of non-Hodgkin's lymphomas (NHLs) accumulate a wild-type form of the p53 tumor suppressor protein at the nuclear level. In normal cells, p53 induction is associated with a temporary cell growth arrest at the G1-S boundary of the cell cycle. This activity of p53 as a G1 checkpoint molecule is strictly dependent on its ability to induce the transcription of the inhibitor of the cyclin dependent kinase, p21. To verify the functionality of the wild-type p53 protein accumulated in NHL cells, 70 cases were comparatively analyzed for p53 and p21 expression and status of the respective genes. Overexpression of the wt p53 protein was associated with the accumulation of p21, indicating that p53 is functional with respect to p21 induction in these tumors. The coaccumulation of p53 with Ki-67 antigen indicates that wt p53-positive cells and p21-positive cells, as well, are actively proliferative elements, supporting the notion that p53-induced, p21-mediated growth arrest is somehow overridden in NHL cells. No p21 mutation or particular allele variant was shown to correlate with p21 protein accumulation, thus excluding a role for p21 structural abnormalities. Taken together, our data suggest the existence in NHL of a peculiar mechanism of functional inactivation of the p53 G1 checkpoint pathway occurring downstream of the CDK inhibitor p21.


Subject(s)
Cyclins/biosynthesis , Gene Expression Regulation, Neoplastic , Lymphoma, Non-Hodgkin/genetics , Neoplasm Proteins/biosynthesis , Transcriptional Activation , Tumor Suppressor Protein p53/biosynthesis , Cell Division , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/genetics , Enzyme Induction , G1 Phase , Genes, p53 , Humans , Ki-67 Antigen/biosynthesis , Ki-67 Antigen/genetics , Lymphoma, Non-Hodgkin/metabolism , Lymphoma, Non-Hodgkin/pathology , Neoplasm Proteins/genetics , Neoplasm Proteins/physiology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/physiology
17.
Int J Cancer ; 74(1): 26-30, 1997 Feb 20.
Article in English | MEDLINE | ID: mdl-9036865

ABSTRACT

The p16/CDKN2(MTS1) gene encoding for the p16 inhibitor of cyclin D/CDK4 complexes is frequently mutated and deleted in a large fraction of melanoma cell lines, and p16 germline mutations have also been observed in familial melanomas. Moreover, a CDK4 gene mutation, responsible for a functional resistance of CDK4 kinase to p16 inhibitory activity, has been described to occur in some cases of familial melanoma. These data strongly support the idea that deregulation of the CDK4/cyclin D pathway, via CDKN2 or CDK4 mutations, is of biological significance in the development of melanoma. To shed light on the role of these alterations in the development and progression of sporadic melanoma, 12 primary melanomas and 9 corresponding metastases were analyzed for CDKN2 and CDK4 gene mutations. Of the 12 primary melanomas analyzed, 4 showed the presence of mutational inactivation of the p 16 protein and 2 carried silent mutations. No metastases showed the presence of CDKN2 mutations, indicating that mutations of this cyclin-dependent kinase inhibitor is not common in the progression of sporadic melanoma. On the other hand, the absence, in the metastases, of the CDKN2 mutation detected in the corresponding primary tumors suggests that 9p21 homozygous deletion may play a major role in the metastatic spreading of this type of tumor. None of the cases analyzed showed the presence of an Arg24Cys mutation, which functionally protects CDK4 from p16 inhibition. This indicates that CDK4 mutation plays a minor role in the development and progression of sporadic melanoma.


Subject(s)
Biomarkers, Tumor/analysis , Carrier Proteins/genetics , Cyclin-Dependent Kinases/genetics , Melanoma/genetics , Melanoma/pathology , Point Mutation , Proto-Oncogene Proteins , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Carrier Proteins/analysis , Carrier Proteins/biosynthesis , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase Inhibitor p16 , Cyclin-Dependent Kinases/analysis , Cyclin-Dependent Kinases/biosynthesis , Exons , Genes, Tumor Suppressor , Humans , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Reference Values
18.
J Pathol ; 181(1): 8-13, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9071997

ABSTRACT

Dedifferentiated liposarcoma represents a distinct subtype of liposarcoma and is characterized by the presence of abrupt transition from well-differentiated liposarcoma to high-grade pleomorphic sarcoma (mostly MFH-like). A key role for p53 in tumour progression of this subset of liposarcomas has been suggested on the basis of p53 immunopositivity. A series of 14 dedifferentiated liposarcomas has been investigated by analysing the p53 gene and protein together with the p53-related molecules p21Waf1 and mdm2, to verify whether the p53 pathway is involved in the development and progression of this tumour type. The results indicate that the p53 gene is rarely involved in dedifferentiated liposarcoma (7 per cent of cases analysed) and that low percentages of p53 immunopositivity are still compatible with integrity of the p53 gene. This concept is also supported by the observed preservation of p21Waf1 immunoreactivity in all but the p53-mutated cases. By contrast, mdm2 overexpression emerges as the most frequent abnormality in dedifferentiated liposarcoma (57 and 78 per cent of cases in well-differentiated and high-grade areas, respectively).


Subject(s)
Genes, p53 , Liposarcoma/genetics , Nuclear Proteins , Cell Differentiation , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Disease Progression , Humans , Immunoenzyme Techniques , Liposarcoma/metabolism , Liposarcoma/pathology , Mutation , Neoplasm Proteins/metabolism , Polymorphism, Single-Stranded Conformational , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-mdm2 , Tumor Suppressor Protein p53/metabolism
20.
Am J Pathol ; 148(4): 1037-45, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8644845

ABSTRACT

Soft tissue sarcomas represent a heterogeneous group of mesenchymal malignancies, and the majority of the previous scientific studies that have analyzed the occurrence of cell cycle regulators aberrations within soft tissue sarcomas have dealt with broad categories of different tumors. As a consequence, data concerning single classes of sarcomas are very limited. The authors analyze herein a histologically homogeneous series of 23 cases of leiomyosarcoma of the deep soft tissue. The p53 pathway was studied by investigating the p53 gene and protein, MDM2 protein, and p21waf1 protein. The Rb-cyclin D pathway was analyzed by studying the Rb gene and protein, p16MTS1/INK4A gene and protein, cyclin D1Prad1/bcl1 and cyclin D3 proteins. Aberrations of the p53 pathway were observed in about 16 percent of cases and were limited to the p53 gene. Such a finding contrasts with the higher rates of p53/MDM2 abnormalities reported in other types of sarcomas such as liposarcoma. Interestingly, abnormalities involving the Rb-cyclin D pathway were detected in about 90 percent of cases. The Rb-cyclin D pathway therefore emerges as the preferred target for molecular abnormalities in this subset of soft tissue sarcomas.


Subject(s)
Genes, Tumor Suppressor , Leiomyosarcoma/genetics , Soft Tissue Neoplasms/genetics , Base Sequence , Genes, p53 , Humans , Immunohistochemistry , Leiomyosarcoma/chemistry , Molecular Sequence Data , Soft Tissue Neoplasms/chemistry , Tumor Suppressor Protein p53/genetics
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