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1.
Bioorg Med Chem Lett ; 30(22): 127551, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-32927028

RESUMEN

Triazolo[4,5-d]pyrimidin-5-amines were identified from kinase selectivity screening as novel ERK3 inhibitors with sub-100 nanomolar potencies in a biochemical assay using MK5 as substrate and with an attractive kinase selectivity profile. ERK3 crystal structures clarified the inhibitor binding mode in the ATP pocket with impact on A-loop, GC-loop and αC-helix conformations suggesting a potential structural link towards MK5 interaction via the FHIEDE motif. The inhibitors also showed sub-100 nM potencies in a cellular ERK3 NanoBRET assay and with excellent correlation to the biochemical IC50s. This novel series provides valuable tool compounds to further investigate the biological function and activation mechanism of ERK3.


Asunto(s)
Proteína Quinasa 6 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Proteína Quinasa 6 Activada por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad
3.
Int J Cancer ; 135(3): 551-62, 2014 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-23165423

RESUMEN

Interleukin-6 (IL-6) is one of the major inflammatory interleukins that has been linked to cancer progression. In our model for human skin squamous cell carcinoma (SCC), IL-6 expression is strongly upregulated upon progression from benign tumors to highly malignant, metastasizing SCCs. We now demonstrate that IL-6 promotes malignant and invasive tumor growth in human skin SCCs by inducing cell type specific cytokine profiles in tumor keratinocytes and stromal fibroblasts, activating the latter towards a tumor associated fibroblast (TAF) phenotype. In three-dimensional organotypic cocultures in vitro invasive growth of IL-6 overexpressing tumor keratinocytes, is associated with increased expression of matrix metalloproteinase-2 (MMP-2), MMP-14 and tissue inhibitor of metalloproteinases-2, and clearly depends on IL-6 activated fibroblasts. IL-6-induced secretion of monocyte chemotactic protein-1 (MCP-1) in tumor keratinocytes and of hepatocyte growth factor in fibroblasts is crucial for regulating expression and activation of MMP-2. This functional role of IL-6 is confirmed in vivo. Here MMP-14 and MMP-2 expression occur exclusively in surface transplants of IL-6 overexpressing keratinocytes and fibroblasts are identified as important source of MMP-2. Our data indicate that tumor keratinocytes derived IL-6 activates stromal fibroblasts towards a TAF phenotype, promoting tumor invasion via enhanced expression and activation of MMP-2.


Asunto(s)
Carcinoma de Células Escamosas/patología , Fibroblastos/patología , Interleucina-6/metabolismo , Queratinocitos/patología , Neoplasias Cutáneas/patología , Células del Estroma/patología , Animales , Carcinoma de Células Escamosas/metabolismo , Adhesión Celular , Comunicación Celular , Movimiento Celular , Células Cultivadas , Técnicas de Cocultivo , Medios de Cultivo Condicionados/farmacología , Fibroblastos/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Hibridación in Situ , Queratinocitos/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Desnudos , Invasividad Neoplásica , Neoplasias Cutáneas/metabolismo , Células del Estroma/metabolismo
5.
J Pathol ; 227(1): 17-28, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22262122

RESUMEN

Inflammation contributes to tumour growth, invasion and angiogenesis. We investigated the contribution of macrophages and their polarization to tumour progression in a model of VEGF-A-induced skin carcinogenesis. Transfection of the human non-tumourigenic keratinocyte cell line HaCaT with murine VEGF-A leads to malignant tumour growth in vivo. The resulting tumours are characterized by extensive vascularization, invasive growth and high numbers of M2-polarized macrophages that crucially contribute to the establishment of the malignant phenotype. Accordingly, macrophage depletion from tumour-bearing animals resulted in reduced tumour growth, inhibition of invasion, decreased proliferation and reduced angiogenesis. In vitro, VEGF-A exerted a chemo-attracting effect on macrophages, but did not induce M2 polarization. We identified IL-4 and IL-10 as the factors involved in M2 polarization. These factors were produced by tumour cells (IL-10) and macrophages (IL-4) in vivo. Addition of recombinant IL-4 and IL-10 in vitro induced a pro-invasive M2 macrophage phenotype and inhibition of the IL-4 receptor in vivo blocked M2 polarization of macrophages, resulting in a less aggressive tumour phenotype. Thus, we provide evidence that M2 macrophages are crucial for the development of VEGF-A-induced skin tumours and that VEGF-A contributes to malignant tumour growth, not only by enhancing angiogenesis but also by establishing an anti-inflammatory microenvironment. However, VEGF-A alone is not sufficient to create a tumour-promoting microenvironment and requires the presence of IL-4 and IL-10 to induce M2 polarization of macrophages.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Macrófagos/patología , Neoplasias Cutáneas/genética , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Células de la Médula Ósea/patología , Línea Celular Transformada , Movimiento Celular , Modelos Animales de Enfermedad , Humanos , Inmunidad Celular , Interleucina-10/metabolismo , Interleucina-10/farmacología , Interleucina-4/metabolismo , Interleucina-4/farmacología , Queratinocitos , Activación de Macrófagos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Trasplante de Neoplasias , Neovascularización Patológica , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Transfección , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo
6.
Clin Cancer Res ; 29(15): 2859-2868, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37223931

RESUMEN

PURPOSE: The majority of gastrointestinal stromal tumors (GIST) are driven by constitutively activated KIT/PDGFRA kinases and are susceptible to treatment with tyrosine kinase inhibitors. During treatment, most of these tumors will develop secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of IDRX-42, a novel selective KIT inhibitor with high activity toward the most relevant KIT mutations, in 4 GIST xenograft models. EXPERIMENTAL DESIGN: NMRI nu/nu mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT:p.K642E), and the cell line-derived model GIST882 (KIT:p.K642E). Mice were treated daily with vehicle (control), imatinib (100 mg/kg), sunitinib (20 mg/kg), avapritinib (5 mg/kg), or IDRX-42 (10 mg/kg, 25 mg/kg). Efficacy was assessed by tumor volume evolution, histopathology, grading of histologic response, and IHC. The Kruskal-Wallis and Wilcoxon matched-pairs tests were used for statistical analysis, with P < 0.05 considered as significant. RESULTS: IDRX-42 (25 mg/kg) caused tumor volume shrinkage in UZLX-GIST25, GIST882, and UZLX-GIST2B, with a relative decrease to 45.6%, 57.3%, and 35.1% on the last day as compared with baseline, and tumor growth delay (160.9%) compared with control in UZLX-GIST9. Compared with controls, IDRX-42 (25 mg/kg) induced a significant decrease in mitosis. In UZLX-GIST25 and GIST882 grade 2-4 histologic response with myxoid degeneration was observed in all IDRX-42 (25 mg/kg)-treated tumors. CONCLUSIONS: IDRX-42 showed significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induced volumetric responses, decreased mitotic activity, and had antiproliferative effects. In models with KIT exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.


Asunto(s)
Antineoplásicos , Tumores del Estroma Gastrointestinal , Humanos , Animales , Ratones , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Xenoinjertos , Proteínas Proto-Oncogénicas c-kit/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Línea Celular Tumoral , Mutación , Resistencia a Antineoplásicos/genética
7.
J Med Chem ; 66(4): 2386-2395, 2023 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-36728508

RESUMEN

The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the KIT gene is a prime example of targeted therapy for treatment of cancer. The approval of the tyrosine kinase inhibitor imatinib has significantly improved patient survival, but emerging resistance under treatment and relapse is observed. Several additional KIT inhibitors have been approved; still, there is a high unmet need for KIT inhibitors with high selectivity and broad coverage of all clinically relevant KIT mutants. An imidazopyridine hit featuring excellent kinase selectivity was identified in a high-throughput screen (HTS) and optimized to the clinical candidate M4205 (IDRX-42). This molecule has a superior profile compared to approved drugs, suggesting a best-in-class potential for recurrent and metastatic GISTs driven by KIT mutations.


Asunto(s)
Antineoplásicos , Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-kit/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Mesilato de Imatinib , Mutación , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Neoplasias Gastrointestinales/tratamiento farmacológico
8.
Am J Pathol ; 176(2): 981-94, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20042679

RESUMEN

Vascular endothelial growth factor (VEGF), which is a key regulator of angiogenesis, often induces formation of immature vessels with increased permeability and reduced vessel functionality. Here, we demonstrate that de novo expression of murine (m)VEGF-164 induces malignant and invasive tumor growth of HaCaT keratinocytes. However, the mVEGF-164-induced tumors are ulcerated with a disorganized epithelium that is interrupted by lacunae with limited basement membrane and endothelial cell coverage. Vessel maturation is strongly impaired. Tumor and vessel micromorphology are markedly improved by the combined expression of human platelet-derived growth factor (hPDGF)-B and mVEGF-164. Although tumor size and malignancy are comparable with either mVEGF-164 alone or combined human PDGF-B and mVEGF-164 expression, combined hPDGF-B and mVEGF-164 expression leads to a more solid and compact tumor tissue with a mature functional tumor vasculature and a higher microvessel density, as demonstrated histologically and by dynamic contrast-enhanced magnetic resonance imaging. Treatment of the hPDGF-B- and mVEGF-164-expressing tumors with imatinib mesylate to block PDGF-B signaling reverses this effect. In addition, tumor cell invasion of mVEGF-164 transfectants and mVEGF-164 plus hPDGF-B transfectants in vivo is associated with a marked induction of tumor-derived matrix metalloproteinase-1 and stromal matrix metalloproteinase-9 and -13, as was confirmed in three-dimensional organotypic co-cultures with fibroblasts in vitro. These data clearly demonstrate the need for a concerted action of different growth factors in the establishment of solid tumors with functional vasculature and emphasize the need for a multifactorial therapy.


Asunto(s)
Carcinoma de Células Escamosas/patología , Neovascularización Patológica/fisiopatología , Proteínas Proto-Oncogénicas c-sis/fisiología , Neoplasias Cutáneas/patología , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Benzamidas , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/ultraestructura , Proliferación Celular , Células Cultivadas , Humanos , Mesilato de Imatinib , Ratones , Ratones Desnudos , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-sis/genética , Pirimidinas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/ultraestructura , Transfección , Trasplante Heterólogo , Carga Tumoral/genética
9.
iScience ; 23(12): 101832, 2020 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-33305187

RESUMEN

Tepotinib is an oral MET inhibitor approved for metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. Examining treatment-naive or tepotinib-resistant cells with MET amplification or METex14 skipping mutations identifies other receptor tyrosine kinases (RTKs) that co-exist in cells prior to tepotinib exposure and become more prominent upon tepotinib resistance. In a small cohort of patients with lung cancer with MET genetic alterations treated with tepotinib, gene copy number gains of other RTKs were found at baseline and affected treatment outcome. An Src homology 2 domain-containing phosphatase 2 (SHP2) inhibitor delayed the emergence of tepotinib resistance and synergized with tepotinib in treatment-naive and tepotinib-resistant cells as well as in xenograft models. Alternative signaling pathways potentially diminish the effect of tepotinib monotherapy, and the combination of tepotinib with an SHP2 inhibitor enables the control of tumor growth in cells with MET genetic alterations.

10.
Cell Rep ; 23(13): 3891-3904, 2018 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-29949772

RESUMEN

Formation of synapses between motor neurons and muscles is initiated by clustering of acetylcholine receptors (AChRs) in the center of muscle fibers prior to nerve arrival. This AChR patterning is considered to be critically dependent on calcium influx through L-type channels (CaV1.1). Using a genetic approach in mice, we demonstrate here that either the L-type calcium currents (LTCCs) or sarcoplasmic reticulum (SR) calcium release is necessary and sufficient to regulate AChR clustering at the onset of neuromuscular junction (NMJ) development. The combined lack of both calcium signals results in loss of AChR patterning and excessive nerve branching. In the absence of SR calcium release, the severity of synapse formation defects inversely correlates with the magnitude of LTCCs. These findings highlight the importance of activity-dependent calcium signaling in early neuromuscular junction formation and indicate that both LTCC and SR calcium release individually support proper innervation of muscle by regulating AChR patterning and motor axon outgrowth.


Asunto(s)
Calcio/metabolismo , Unión Neuromuscular/fisiología , Proyección Neuronal/fisiología , Receptores Colinérgicos/metabolismo , Animales , Canales de Calcio Tipo L/deficiencia , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Diafragma/metabolismo , Embrión de Mamíferos/metabolismo , Desarrollo Fetal , Ratones , Ratones Noqueados , Neuronas Motoras/fisiología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/deficiencia , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo
11.
Nat Commun ; 9(1): 21, 2018 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-29295986

RESUMEN

Cancer cell dissemination during very early stages of breast cancer proceeds through poorly understood mechanisms. Here we show, in a mouse model of HER2+ breast cancer, that a previously described sub-population of early-evolved cancer cells requires macrophages for early dissemination. Depletion of macrophages specifically during pre-malignant stages reduces early dissemination and also results in reduced metastatic burden at end stages of cancer progression. Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206+/Tie2+ macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2+ early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.


Asunto(s)
Neoplasias de la Mama/patología , Macrófagos/patología , Animales , Progresión de la Enfermedad , Femenino , Ratones , Metástasis de la Neoplasia , Células RAW 264.7 , Receptor ErbB-2/genética , Vía de Señalización Wnt
12.
Sci Rep ; 6: 20050, 2016 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-26831464

RESUMEN

In mature skeletal muscle, the intracellular Ca(2+) concentration rises dramatically upon membrane depolarization, constituting the link between excitation and contraction. This process requires Ca(2+) release from the sarcoplasmic reticulum via the type 1 ryanodine receptor (RYR1). However, RYR1's potential roles in muscle development remain obscure. We used an established RyR1- null mouse model, dyspedic, to investigate the effects of the absence of a functional RYR1 and, consequently, the lack of RyR1-mediated Ca(2+) signaling, during embryogenesis. Homozygous dyspedic mice die after birth and display small limbs and abnormal skeletal muscle organization. Skeletal muscles from front and hind limbs of dyspedic fetuses (day E18.5) were subjected to microarray analyses, revealing 318 differentially expressed genes. We observed altered expression of multiple transcription factors and members of key signaling pathways. Differential regulation was also observed for genes encoding contractile as well as muscle-specific structural proteins. Additional qRT-PCR analysis revealed altered mRNA levels of the canonical muscle regulatory factors Six1, Six4, Pax7, MyoD, MyoG and MRF4 in mutant muscle, which is in line with the severe developmental retardation seen in dyspedic muscle histology analyses. Taken together, these findings suggest an important non-contractile role of RyR1 or RYR1-mediated Ca(2+) signaling during muscle organ development.


Asunto(s)
Señalización del Calcio , Embrión de Mamíferos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Desarrollo de Músculos , Músculo Esquelético/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/deficiencia , Animales , Perfilación de la Expresión Génica , Ratones , Ratones Noqueados , Proteínas Musculares/biosíntesis , Proteínas Musculares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos
13.
Cancer Med ; 2(2): 117-29, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23634280

RESUMEN

Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes tumor progression in different tumor models in an autocrine and paracrine manner. However, at the same time GM-CSF is used in cancer therapies to ameliorate neutropenia. We have previously shown in GM-CSF and G-CSF expressing or negative skin or head and neck squamous cell carcinoma that GM-CSF expression is associated with a highly angiogenic and invasive tumor phenotype. To determine the functional contribution of GM-CSF to tumor invasion, we stably transfected a GM-CSF negative colon adenocarcinoma cell line HT-29 with GM-CSF or treated the same cell line with exogenous GM-CSF. While GM-CSF overexpression and treatment reduced tumor cell proliferation and tumor growth in vitro and in vivo, respectively, it contributed to tumor progression. Together with an enhanced migratory capacity in vitro, we observed a striking increase in tumor cell invasion into the surrounding tissue concomitant with the induction of an activated tumor stroma in GM-CSF overexpressing or GM-CSF treated tumors. In a complex 3D in vitro model, enhanced GM-CSF expression was associated with a discontinued basement membrane deposition that might be mediated by the increased expression and activation of MMP-2, -9, and -26. Treatment with GM-CSF blocking antibodies reversed this effect. The increased presence and activity of these tumor cell derived proteases was confirmed in vivo. Here, expression of MMP-26 protein was predominantly located in pre- and early-invasive areas suggesting MMP-26 expression as an early event in promoting GM-CSF dependent tumor invasion.


Asunto(s)
Adenocarcinoma/patología , Neoplasias del Colon/patología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasas de la Matriz Secretadas/metabolismo , Adenocarcinoma/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias del Colon/metabolismo , Regulación Neoplásica de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Células HT29 , Humanos , Ratones , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Neovascularización Patológica , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo
14.
PLoS One ; 7(7): e40058, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22792213

RESUMEN

Tumor progression is controlled by signals from cellular and extra-cellular microenvironment including stromal cells and the extracellular matrix. Consequently, three-dimensional in vitro tumor models are essential to study the interaction of tumor cells with their microenvironment appropriately in a biologically relevant manner. We have previously used organotypic co-cultures to analyze the malignant growth of human squamous cell carcinoma (SCC) cell lines on a stromal equivalent in vitro. In this model, SCC cell lines are grown on a collagen-I gel containing fibroblasts. Since macrophages play a critical role in the progression of many tumor types, we now have expanded this model by integrating macrophages into the collagen gel of these organotypic tumor co-cultures. This model was established as a murine and a human system of skin SCCs. The effect of macrophages on tumor progression depends on their polarization. We demonstrate that macrophage polarization in organotypic co-cultures can be modulated towards and M1 or an M2 phenotype by adding recombinant IFN-γ and LPS or IL-4 respectively to the growth medium. IL-4 stimulation of macrophage-containing cultures resulted in enhanced tumor cell invasion evidenced by degradation of the basement membrane, enhanced collagenolytic activity and increased MMP-2 and MMP-9. Interestingly, extended co-culture with tumor cells for three weeks resulted in spontaneous M2 polarization of macrophages without IL-4 treatment. Thus, we demonstrate that macrophages can be successfully integrated into organotypic co-cultures of murine or human skin SCCs and that this model can be exploited to analyze macrophage activation towards a tumor supporting phenotype.


Asunto(s)
Técnicas de Cultivo de Célula/métodos , Macrófagos/patología , Técnicas de Cultivo de Tejidos/métodos , Animales , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Humanos , Interleucina-4/farmacología , Macrófagos/efectos de los fármacos , Ratones , Invasividad Neoplásica , Células Tumorales Cultivadas
16.
Nucleus ; 1(4): 343-53, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21327083

RESUMEN

Association of nuclear lamins with the inner nuclear membrane (INM) is mediated by lipid modifications: either by C-terminal isoprenylation or N-terminal myristoylation. Overexpression of lamins or other lipidated nuclear proteins induces the formation of intranuclear membrane-like arrays. Lamin-induced intranuclear array formation has been observed in Xenopus oocytes as well as in mammalian tissue culture cells. With the use of a membrane-specific fluorescence dye we show here that these arrays are made up of typical lipid membranes. While continuity between these intranuclear membranes and the INM has not been observed so far the presence of integral as well as luminal marker proteins of the endoplasmic reticulum (ER) indicates that these membranes are derived from the nuclear membrane/ER compartment. Earlier studies demonstrated that overexpression of integral membrane proteins of the INM can induce formation of intranuclear membranes, which bud from the INM. Integral membrane proteins reach the INM via the pore membranes while lipidated proteins are imported into the nucleoplasm via the classical NLS pathway where they interact with the INM via their lipid moieties. Together with the previously published data our results show that the formation of intranuclear membranes follows similar routes irrespective of whether the proteins triggering membrane formation are integral membrane or lipidated proteins.


Asunto(s)
Proteínas de la Membrana/metabolismo , Membrana Nuclear/metabolismo , Animales , Células COS , Chlorocebus aethiops , Retículo Endoplásmico/metabolismo , Colorantes Fluorescentes/química , Laminas/metabolismo , Lípidos de la Membrana/metabolismo , Modelos Moleculares , Ácido Mirístico/metabolismo , Proteínas Nucleares/metabolismo , Oocitos/metabolismo , Xenopus/crecimiento & desarrollo , Xenopus/metabolismo
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