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1.
AJNR Am J Neuroradiol ; 40(6): E32, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31072977
2.
AJNR Am J Neuroradiol ; 40(2): 366-369, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30573459

RESUMO

High-grade gliomas in patients with neurofibromatosis type 1 are rare and may therefore not be considered in the differential of brain lesions. Here, we describe 5 children with neurofibromatosis type 1; four of them developed various types of high-grade gliomas. The fifth patient had imaging features concerning for a high-grade lesion, but tissue diagnosis showed a low-grade glioma. The cases and literature summary provided here are to raise awareness for the occurrence of high-grade gliomas in children with neurofibromatosis type 1 and the limited ability of imaging features alone to predict a high-grade malignancy.


Assuntos
Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/patologia , Glioma/etiologia , Glioma/patologia , Neurofibromatose 1/complicações , Criança , Pré-Escolar , Feminino , Humanos , Masculino
3.
Oncogene ; 35(42): 5552-5564, 2016 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-27086929

RESUMO

High-level amplification of the protein phosphatase PPM1D (WIP1) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1 overexpression increased expression of Shh target genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor cells in a p53-independent manner. Thus, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter (ND2:WIP1). The external granule layer (EGL) in early postnatal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. MB incidence increased and survival decreased when ND2:WIP1 mice were crossed with an Shh-activated MB mouse model. Conversely, Wip1 knockout significantly suppressed MB formation in two independent mouse models of Shh-activated MB. Furthermore, Wip1 knockdown or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHH pathway-inhibiting drugs in Shh-activated MB cells in vitro. This suggests an important cross-talk between SHH and WIP1 pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB.


Assuntos
Neoplasias Cerebelares/metabolismo , Proteínas Hedgehog/metabolismo , Meduloblastoma/metabolismo , Células-Tronco Neurais/metabolismo , Proteína Fosfatase 2C/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Transgênicos , Células NIH 3T3 , Proteína Fosfatase 2C/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Oncogene ; 34(9): 1126-40, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-24632620

RESUMO

Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified upregulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1α activated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knockdown inhibited medulloblastoma growth and invasion. WIP1 knockdown also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knockdown inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knockdown inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4 and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate crosstalk among WIP1, CXCR4 and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.


Assuntos
Neoplasias Cerebelares/patologia , Quimiocina CXCL2/metabolismo , Quinase 5 de Receptor Acoplado a Proteína G/metabolismo , Meduloblastoma/patologia , Fosfoproteínas Fosfatases/genética , Receptores CXCR4/genética , Adolescente , Animais , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , Criança , Pré-Escolar , Feminino , Quinase 5 de Receptor Acoplado a Proteína G/genética , Humanos , Lactente , Masculino , Meduloblastoma/genética , Camundongos , Camundongos SCID , Invasividade Neoplásica , Transplante de Neoplasias , Fosfoproteínas Fosfatases/metabolismo , Proteína Fosfatase 2C , Receptores CXCR4/metabolismo , Transdução de Sinais , Adulto Jovem
5.
Curr Med Chem ; 20(19): 2486-99, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23531216

RESUMO

The standard targeted therapy for HER2-overexpressing breast cancer is the HER2 monoclonal antibody, trastuzumab. Although effective, many patients eventually develop trastuzumab resistance. The dual EGFR/HER2 small molecule tyrosine kinase inhibitor lapatinib is approved for use in trastuzumab-refractory metastatic HER2-positive breast cancer. However, lapatinib resistance is a problem as most patients with trastuzumab-refractory disease do not benefit from lapatinib. Understanding the mechanisms underlying lapatinib resistance may ultimately facilitate development of new therapeutic strategies for HER2-overexpressing breast cancer. Our current results indicate that MEK inhibition increases lapatinib-mediated cytotoxicity in resistant HER2-overexpressing breast cancer cells. We genetically and pharmacologically blocked MEK/ERK signaling and evaluated lapatinib response by trypan blue exclusion, anchorage-independent growth assays, flow cytometric cell cycle and apoptosis analysis, and in tumor xenografts. Combined MEK inhibition and lapatinib treatment reduced phosphorylated ERK more than single agent treatment. In addition, Western blots, immunofluorescence, and immunohistochemistry demonstrated that the combination of MEK inhibitor plus lapatinib reduced nuclear expression of the MEK/ERK downstream proto-oncogene FOXM1. Genetic knockdown of MEK was tested for the ability to increase lapatinib-mediated cell cycle arrest or apoptosis in JIMT-1 and MDA361 cells. Finally, xenograft studies demonstrated that combined pharmacological inhibition of MEK plus lapatinib suppressed tumor growth and reduced expression of FOXM1 in HER2-overexpressing breast cancers that are resistant to trastuzumab and lapatinib. Our results suggest that FoxM1 contributes to lapatinib resistance downstream of MEK signaling, and supports further study of pharmacological MEK inhibition to improve response to lapatinib in HER2-overexpressing trastuzumab-resistant breast cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Mama/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Proteína Forkhead Box M1 , Fatores de Transcrição Forkhead/análise , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Proto-Oncogene Mas , Quinazolinas/farmacologia
6.
Curr Pharm Des ; 15(4): 380-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19199965

RESUMO

Angiogenesis is tightly regulated by opposing mechanisms in mammalian cells and is controlled by the angiogenic switch. Other review articles have described a central role for the PTEN/PI-3 kinase/AKT signaling node in the coordinate control of cell division, tumor growth, apoptosis, invasion and cellular metabolism [1, 2]. In this review, we focus on literature that supports the PTEN/PI-3 kinase/AKT signaling node as a major control point for the angiogenic switch in both the on and off positions. We also discuss the rationale for designing small molecule drugs that target the PTEN/PI-3 kinase/AKT signaling node for therapeutic intervention. Our hypothesis is that, instead of inhibiting one cell surface receptor, such as VEGFR2 with bevacizumab (Avastin), thereby leaving a significant number of receptors free to pulse angiogenic signals, a more effective strategy may be to regulate signaling through an intercept node where redundant cell surface receptor signals converge to transmit important signaling events within the cell. This therapeutic configuration brings coordinate control over multiple cell surface receptors in concert with a physiologic response which may combine arrest of cell cycle progression with growth inhibition and the induction of genes involved in specialized functions such as movement, which are all required for the complex process of angiogenesis to occur in a temporal-spatial paradigm.


Assuntos
Neovascularização Patológica , Neovascularização Fisiológica , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Animais , Humanos , PTEN Fosfo-Hidrolase/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia
7.
Cancer Chemother Pharmacol ; 45(4): 345-9, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10755324

RESUMO

PURPOSE: To further evaluate the activity of irinotecan (CPT-11) plus 1,3-bis-(chloroethyl)-1-nitrosourea (BCNU) in the treatment of central nervous system tumor-derived xenografts in athymic nude mice. METHODS: We report studies evaluating the schedule-dependence of this regimen in the treatment of the malignant glioma xenograft D-54 MG. RESULTS: The combination of BCNU and CPT-11 showed the highest enhancement index (2.0-3.3) when BCNU was given on day 1 and CPT-11 was given on days 1-5 and 8-12. Delay of CPT-11 administration to day 3 or day 5 substantially decreased activity with enhancement indices of 1.6-1.8 and 0.6-1.0, respectively. Delay of BCNU administration to day 8 also reduced the CPT-11 activity with enhancement indices of 1.2-1.4. CONCLUSIONS: These results suggest that the presence of a BCNU-induced adduct or possibly crosslink prior to administration of CPT-11 is critical for enhanced activity. Although the mechanism of this enhancement is not currently known, a phase I trial of CPT-11 plus BCNU for adults with recurrent malignant glioma based on these results is in progress.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/análogos & derivados , Carmustina/uso terapêutico , Glioma/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/patologia , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Carmustina/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Glioma/patologia , Humanos , Irinotecano , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Transplante Heterólogo
8.
Adv Exp Med Biol ; 430: 29-37, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9330716

RESUMO

A recently discovered class of ancillary subunits has been shown to modify the inactivation properties of alpha-subunits belonging to the Kv1 family of potassium channels. One of these subunits, Kv beta 1.2, modifies intrinsic alpha-subunit C-type inactivation. N-type inactivation and open channel block have been proposed to increase the rate of development of C-type inactivation. We demonstrate here that Kv beta 1.2 has kinetic properties which are consistent with rapid open channel block.


Assuntos
Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/fisiologia , Animais , Simulação por Computador , Condutividade Elétrica , Furões , Ativação do Canal Iônico/fisiologia , Cinética , Canal de Potássio Kv1.2 , Canal de Potássio Kv1.4 , Substâncias Macromoleculares , Canais de Potássio/química
9.
J Physiol ; 489 ( Pt 3): 709-21, 1995 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-8788936

RESUMO

1. A fast inactivating transient K+ current (FK1) cloned from ferret ventricle and expressed in Xenopus oocytes was studied using the two-electrode voltage clamp technique. Removal of the NH2-terminal domain of FK1 (FK1 delta 2-146) removed fast inactivation consistent with previous findings in Kv1.4 channels. The NH2-terminal deletion mutation revealed a slow inactivation process, which matches the criteria for C-type inactivation described for Shaker B channels. 2. Inactivation of FK1 delta 2-146 at depolarized potentials was well described by a single exponential process with a voltage-insensitive time constant. In the range -90 to +20 mV, steady-state C-type inactivation was well described by a Boltzmann relationship that compares closely with inactivation measured in the presence of the NH2-terminus. These results suggest that C-type inactivation is coupled to activation. 3. The coupling of C-type inactivation to activation was assessed by mutation of the fourth positively charged residue (arginine 454) in the S4 voltage sensor to glutamine (R454Q). This mutation produced a hyperpolarizing shift in the inactivation relationship of both FK1 and FK1 delta 2-146 without altering the rate of inactivation of either clone. 4. The rates of recovery from inactivation are nearly identical in FK1 and FK1 delta 2-146. 5. To assess the mechanisms underlying recovery from inactivation the effects of elevated [K+]o and selective mutations in the extracellular pore and the S4 voltage sensor were compared in FK1 and FK1 delta 2-146. The similarity in recovery rates in response to these perturbations suggests that recovery from C-type inactivation governs the overall rate of recovery of inactivated channels for both FK1 and FK1 delta 2-146. 6. Analysis of the rate of recovery of FK1 channels for inactivating pulses of different durations (70-2000 ms) indicates that recovery rate is insensitive to the duration of the inactivating pulse.


Assuntos
Miocárdio/metabolismo , Oócitos/metabolismo , Canais de Potássio/metabolismo , Animais , Sequência de Bases , Clonagem Molecular , Feminino , Furões , Coração/efeitos dos fármacos , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Cinética , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Dados de Sequência Molecular , Mutação , Oócitos/efeitos dos fármacos , Técnicas de Patch-Clamp , Canais de Potássio/efeitos dos fármacos , RNA Complementar/metabolismo , Xenopus
10.
Am J Physiol ; 269(1 Pt 2): H385-91, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7631872

RESUMO

In mammals, voltage-gated K+ channels can be made of complexes containing alpha-subunits similar to the Shaker K+ channel and smaller cytoplasmic beta-subunits. Recent studies have suggested that these ancillary beta-subunits can modulate K+ channel gating properties. We studied the effects of a K+ channel beta-subunit, Kv beta 3, coexpressed with a Kv1.4 alpha-subunit, FK1, on the time and voltage dependence of channel activation, inactivation, recovery from inactivation, and deactivation, using an oocyte expression system. Kv beta 3 was found to accelerate both the fast and the slow component of Kv1.4 inactivation. Kv beta 3 also altered the relative contributions of the two components of inactivation by increasing the contribution of the slow component to the inactivation process. Kv beta 3 slowed recovery from inactivation for Kv1.4, but not for a Kv1.4 deletion mutant lacking N-type inactivation. Finally, steady-state activation and the time course of Kv1.4 current activation were not strongly influenced by Kv beta 3; however, deactivation was slowed in the presence of Kv beta 3. This study suggests that Kv beta 3 alters channel states which follow activation.


Assuntos
Clonagem Molecular , Ativação do Canal Iônico , Miocárdio/metabolismo , Canais de Potássio/química , Canais de Potássio/fisiologia , Animais , Eletrofisiologia , Furões , Ventrículos do Coração , Oócitos/metabolismo , Fatores de Tempo , Xenopus laevis
11.
J Physiol ; 485 ( Pt 1): 59-71, 1995 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-7658383

RESUMO

1. Using the two-microelectrode, 'cut open' oocyte, and 'torn off' macropatch voltage clamp techniques, we studied the blocking effects of 4-aminopyridine (4-AP) on two cloned K+ channels expressed in Xenopus oocytes, an inactivating K+ channel isolated from ferret ventricle (FK1), and its NH2-terminal deletion mutant (delta NCO) which lacks fast N-type inactivation. 2. Experiments with a permanently charged, impermeant 4-AP derivative, 4-aminopyridine-methyliodide, indicated that the cationic form of 4-AP blocks at an intracellular site. 3. Block accumulated from pulse to pulse and was sensitive to the applied potential during hyperpolarizing deactivating pulses, indicating trapping of 4-AP in deactivated channels. For long trains of depolarizing pulses (-90 to +50 mV, 0.1 Hz), 4-AP block increased with decreasing pulse duration. Block of FK1 was much more sensitive to pulse duration than was block of delta NCO, consistent with competition between N-type inactivation and 4-AP binding. 4. To elucidate these mechanisms further, in the absence of fast N-type inactivation the following results were obtained on delta NCO channels: (1) application of 4-AP caused the appearance of apparent inactivation; (2) 4-AP, however, did not cause cross-over of deactivating tail currents; (3) 4-AP block developed with time for potentials positive to -40 mV; and (4) trapping of 4-AP by delta NCO was insensitive to the degree of C-type inactivation. 5. We conclude that the kinetics of 4-AP block of FK1 and delta NCO channels cannot be accounted for by either a pure open channel or closed channel blocking scheme.


Assuntos
4-Aminopiridina/farmacologia , Miocárdio/metabolismo , Oócitos/metabolismo , Canais de Potássio/efeitos dos fármacos , Animais , Eletrofisiologia , Feminino , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Microeletrodos , Conformação Molecular , Miocárdio/citologia , Oócitos/efeitos dos fármacos , RNA Complementar/biossíntese , Xenopus laevis
12.
J Biol Chem ; 270(11): 6272-7, 1995 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-7890764

RESUMO

Voltage-gated potassium channel beta subunits are cytoplasmic proteins that co-purify with the pore-forming alpha subunits. One of these subunits, Kv beta 1 from rat brain, was previously demonstrated to increase the rate of inactivation of Kv1.1 and Kv1.4 when co-expressed in Xenopus oocytes. We have cloned and characterized a novel voltage-gated K+ channel beta subunit. The cDNA, designated Kv beta 3, has a 408-amino acid open reading frame. It possesses a unique 79-amino acid N-terminal leader, but is identical with rat Kv beta 1 over the 329 C-terminal amino acids. The Kv beta 3 transcript was found in many tissues, but was most abundant in aorta and left ventricle of the heart. Co-expression of Kv beta 3 with K+ channel alpha subunits shows that this beta subunit can increase the rate of inactivation from 4- to 7-fold in a Kv1.4 or Shaker B channel. Kv beta 3 had no effect on Kv1.1, unlike Kv beta 1 which can increase rate of inactivation of this alpha subunit more than 100-fold. Other kinetic parameters were unaffected. This study shows that voltage-gated K+ channel beta subunits are present outside the central nervous system, and that at least one member of this family selectively modulates inactivation of K+ channel alpha subunits.


Assuntos
Ativação do Canal Iônico/fisiologia , Canais de Potássio/fisiologia , Sequência de Aminoácidos , Animais , Aorta/metabolismo , Sequência de Bases , Bovinos , Clonagem Molecular , Primers do DNA , Furões , Expressão Gênica , Ventrículos do Coração , Humanos , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta , Substâncias Macromoleculares , Potenciais da Membrana , Dados de Sequência Molecular , Miocárdio/metabolismo , Técnicas de Patch-Clamp , Reação em Cadeia da Polimerase , Bloqueadores dos Canais de Potássio , Canais de Potássio/biossíntese , RNA Mensageiro/metabolismo , Ratos , Homologia de Sequência de Aminoácidos , Transcrição Gênica
13.
Adv Exp Med Biol ; 382: 11-22, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8540388

RESUMO

We studied the blocking effects of 4-aminopyridine (4-AP) on a Kv1.4 K+ channel. A permanently charged 4-AP derivative only produced block when applied intracellularly. 4-AP block accumulated from pulse to pulse indicating trapping of 4-AP in deactivated channels. For long trains of depolarizing pulses, 4-AP block increased with decreasing pulse duration. This increase took many pulses (> 10) to accumulate and was relieved by two to three subsequent pulses of 500 msec duration. We conclude that the time- and voltage-dependence of 4-AP block can not be accounted for solely by either simple pure open channel or pure closed channel blocking schemes. We propose that the data can be explained by a model in which 4-AP binding is most stable when the channel has a symmetric arrangement in the binding regions.


Assuntos
4-Aminopiridina/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Miocárdio/metabolismo , Bloqueadores dos Canais de Potássio , Animais , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Eletrofisiologia , Furões , Canais de Potássio/genética , Xenopus laevis
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