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1.
Genes Dev ; 36(9-10): 582-600, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35654454

RESUMEN

One of the mechanisms by which cancer cells acquire hyperinvasive and migratory properties with progressive loss of epithelial markers is the epithelial-to-mesenchymal transition (EMT). We have previously reported that in different cancer types, including nonsmall cell lung cancer (NSCLC), the microRNA-183/96/182 cluster (m96cl) is highly repressed in cells that have undergone EMT. In the present study, we used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of Kras mutant autochthonous lung adenocarcinomas. In contrast, ectopic expression of the m96cl in NSCLC cells results in a robust suppression of migration and invasion in vitro, and tumor growth and metastasis in vivo. Detailed immune profiling of the tumors revealed a significant enrichment of activated CD8+ cytotoxic T lymphocytes (CD8+ CTLs) in m96cl-expressing tumors, and m96cl-mediated suppression of tumor growth and metastasis was CD8+ CTL-dependent. Using coculture assays with naïve immune cells, we show that m96cl expression drives paracrine stimulation of CD8+ CTL proliferation and function. Using tumor microenvironment-associated gene expression profiling, we identified that m96cl elevates the interleukin-2 (IL2) signaling pathway and results in increased IL2-mediated paracrine stimulation of CD8+ CTLs. Furthermore, we identified that the m96cl modulates the expression of IL2 in cancer cells by regulating the expression of transcriptional repressors Foxf2 and Zeb1, and thereby alters the levels of secreted IL2 in the tumor microenvironment. Last, we show that in vivo depletion of IL2 abrogates m96cl-mediated activation of CD8+ CTLs and results in loss of metastatic suppression. Therefore, we have identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , MicroARNs , Animales , Linfocitos T CD8-positivos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Interleucina-2/genética , Interleucina-2/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Linfocitos T Citotóxicos , Microambiente Tumoral
2.
Chemistry ; 30(22): e202400033, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38345998

RESUMEN

Herein, BPC catalyzed visible-light-triggered target-specific late-stage solution phase desulfonylation from tryptophan in oligopeptides is portrayed by overcoming the isolation issue up to octamers. This robust and mild method is highly predictable and chemoselective, tolerating myriad of functional groups in aza-heteroaromatics and peptides. Interestingly, reductive desulfonylation is also amenable to biologically significant reactive histidine and tyrosine side chains, signifying the versatility of the strategy. Additional efficacy of BPC is demonstrated by solution phase phenacyl deprotection from C-terminal in peptides. Furthermore, excellent catalyst loading of 0.5 mol% and recyclability demonstrate the practical utility and applicability of this strategy.


Asunto(s)
Oligopéptidos , Péptidos , Péptidos/química , Triptófano/química , Tirosina/química , Histidina/química
3.
Org Biomol Chem ; 20(15): 3029-3042, 2022 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-35332905

RESUMEN

Indoles are one of the most prominent aromatic heterocycles in the organic chemistry field. Due to their widespread presence in various natural products, alkaloids, drugs, approved medicines, etc. the synthesis and functionalization of indoles are of great interest. This review emphasizes recent developments and techniques in the domino cascade cyclization process in the last decade starting from the various building blocks. In particular, this review depicts several intriguing benzannulation methods of creating a benzene ring on a pre-existing pyrrole nucleus in an inter/intramolecular fashion under metal-catalyzed/metal-free approaches. Different subsections focus on gradual timely developments in this complementary area and a detailed analysis of the mechanisms and reactivity patterns. As a complementary method, this review gives a significant incentive to various annulation strategies and also gives an overview of the remaining challenges and upcoming possibilities.


Asunto(s)
Alcaloides , Productos Biológicos , Productos Biológicos/química , Ciclización , Indoles/química , Pirroles/química
4.
J Org Chem ; 84(24): 16003-16012, 2019 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-31747752

RESUMEN

A Brønsted acid-catalyzed pinacol-type rearrangement pathway is reported here to synthesize various substituted α-(3-indolyl) ketones by employing unprotected indoles and α-hydroxy aldehydes as coupling partners. Utilization of economic and readily available Brønsted acid catalyst and use of simple starting precursors exemplify the economic viability of this method. Under this developed protocol, selective migration of aryl over alkyl or a second aryl group is observed depending upon the migratory aptitude of the substituents. Applicability of this method was further demonstrated by synthesizing highly substituted carbazoles through a simple extension of this method to one-pot cascade annulation strategy.

5.
Chem Sci ; 15(33): 13466-13474, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39183925

RESUMEN

The development of highly reducing photocatalysts to functionalize arenes via the generation of reactive aryl radicals under mild and environmentally benign reaction conditions has emerged as a noteworthy approach in the realm of organic synthesis. Herein, we report a readily synthesized series of novel naphthocarbazole derivatives (NCs) as organo-photocatalysts, which, upon irradiation under 390 nm light, acquire high reducing power to catalyze several reductive transformations. The promising properties revealed by in depth photophysical and electrochemical studies ( = -1.9 V to -2.07 V vs. SCE, τ = 5.59 to 7.12 ns) demonstrate NCs to be versatile catalysts, and notably, rational variation of the substituents (NC1-NC6) modulates their success as efficient photoreductants. Detailed DFT calculations of the frontier MO diagrams and energy levels revealed them to be non-donor-acceptor type molecular scaffolds. The applicability of the NCs as catalysts was demonstrated in reductive dehalogenative borylation, phosphorylation, and dehydrohalide intramolecular C-C coupling reactions, as well as the dimerization of carbonyls and imines. Visible-light-irradiated selective reductive desulfonylation from heteroaromatics and peptides further enhances their synthetic utility.

6.
Org Lett ; 26(8): 1705-1710, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38373273

RESUMEN

A new series of carbazole-cored biomimetic ortho-quinone catalysts structurally resembling carbazoquinocin alkaloids have been introduced to promote tunable, metal cocatalyst-free, organocatalytic, dehydrogenative amine oxidation under aerobic conditions. Differently substituted benzyl amines were tolerated under optimized conditions to provide imines in excellent yields. Further efficacy of the catalyst was demonstrated by synthesizing cross-coupled imines efficiently. Control experiments and in-depth DFT studies disclosed a covalent transamination pathway as a plausible mechanism for this newly developed catalytic system.

7.
J Cell Sci ; 124(Pt 12): 2096-106, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21610092

RESUMEN

Keratins 8 and 18 (K8 and K18) are predominantly expressed in simple epithelial tissues and perform both mechanical and regulatory functions. Aberrant expression of K8 and K18 is associated with neoplastic progression and invasion in squamous cell carcinomas (SCCs). To understand the molecular basis by which K8 promotes neoplastic progression in oral SCC (OSCC), K8 expression was inhibited in AW13516 cells. The K8-knockdown clones showed a significant reduction in tumorigenic potential, which was accompanied by a reduction in cell motility, cell invasion, decreased fascin levels, alterations in the organization of the actin cytoskeleton and changes in cell shape. Furthermore, K8 knockdown led to a decrease in α6ß4 integrin levels and α6ß4-integrin-dependent signalling events, which have been reported to play an important role in neoplastic progression in epithelial tissues. Therefore, modulation of α6ß4 integrin signalling might be one of the mechanisms by which K8 and K18 promote malignant transformation and/or progression in OSCCs.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Integrina alfa6beta4/metabolismo , Queratina-18/metabolismo , Queratina-8/metabolismo , Animales , Carcinoma de Células Escamosas/patología , División Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Progresión de la Enfermedad , Humanos , Queratina-18/deficiencia , Queratina-8/deficiencia , Ratones , Ratones Desnudos , Ratones SCID , Invasividad Neoplásica , Transducción de Señal
8.
Org Lett ; 25(48): 8622-8627, 2023 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-38032281

RESUMEN

A masked-bay-region selective first-row transition-metal Cp*Co(III)-catalyzed annulative π-extension of arene-derived ketones is achieved to afford K-region-functionalized benzo[e]pyrenes, benzotetraphenes, and pyrenes. Comprehensive density functional theory studies buttress the mechanistic pathway comprising key steps like peri-C-H activation, alkyne 1,2-migratory insertion, and nucleophilic attack toward ketone, this attack being the rate-determining step. In addition, π-conjugated 1,1'-bipyrenes, potential photocatalyst pyrene-quinones, and putative n-type semiconductor cyano group-containing dibenzo[de,qr]tetracenes are also accessed.

9.
Sci Adv ; 9(30): eadf6210, 2023 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-37494452

RESUMEN

KRAS/ERK pathway phosphorylates DICER1, causing its nuclear translocation, and phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. While DICER1 canonically regulates microRNAs (miRNA) and epithelial-to-mesenchymal transition (EMT), we found that phosphorylated nuclear DICER1 (phospho-nuclear DICER1) promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Instead, we observe that the murine AT2 tumor cells exhibit altered chromatin compaction, and cells from disorganized advanced tumors, but not localized tumors, express gastric genes. Collectively, this results in subpopulations of tumor cells transitioning from a restricted alveolar to a broader endodermal lineage state. In human LUADs, we observed expression of phospho-nuclear DICER1 in advanced tumors together with the expression of gastric genes. We define a multimeric chromatin-DICER1 complex composed of the Mediator complex subunit 12, CBX1, MACROH2A.1, and transcriptional regulators supporting the model that phospho-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , MicroARNs , Humanos , Ratones , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Cromatina/genética , MicroARNs/genética , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Ribonucleasa III/genética , Ribonucleasa III/metabolismo , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo
10.
Mol Cancer Res ; 2023 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-37171981

RESUMEN

Epithelial-to-mesenchymal transition results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. The transcription repressor zinc finger E-box-binding homeobox 1 (ZEB1) binds to E-boxes of gene promoter regions to suppress the expression of epithelial genes. ZEB1 has inconsistent molecular weights, which have been attributed to post-translational modifications (PTMs). We performed mass spectrometry and identified K811 acetylation as a novel PTM in ZEB1. To define the role of ZEB1 acetylation in regulating function, we generated ZEB1 acetyl-mimetic (K811Q) and acetyl-deficient (K811R) mutant-expressing non-small cell lung cancer cell lines (NSCLC). We demonstrate that the K811R ZEB1 (125 kDa) has a shorter protein half-life than wild-type (WT) ZEB1 and K811Q ZEB1 (&tilde225 kDa), suggesting that lack of ZEB1 acetylation in the lower molecular weight form affects protein stability. Further, the acetylated form of ZEB1 recruits the nucleosome remodeling and deacetylase (NuRD) complex to bind the promoter of its target genes mir200c-141 and SEMA3F. RNA-sequencing revealed that WT ZEB1 and K811Q ZEB1 downregulate the expression of epithelial genes to promote lung adenocarcinoma invasion and metastasis, while the K811R ZEB1 does not. Our findings establish that the K811 acetylation promotes ZEB1 protein stability, interaction with other protein complexes, and subsequent invasion/metastasis of lung adenocarcinoma via epithelial-to-mesenchymal transition. Implications: The molecular mechanisms by which ZEB1 is regulated by K811 acetylation to promote protein stability, NuRD complex and promoter interactions, and function are relevant to the development of treatment strategies to prevent and treat metastasis in NSCLC patients.

11.
Mol Cancer Res ; 21(8): 779-794, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37255406

RESUMEN

Epithelial-to-mesenchymal transition results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. The transcription repressor zinc finger E-box-binding homeobox 1 (ZEB1) binds to E-boxes of gene promoter regions to suppress the expression of epithelial genes. ZEB1 has inconsistent molecular weights, which have been attributed to posttranslational modifications (PTM). We performed mass spectrometry and identified K811 acetylation as a novel PTM in ZEB1. To define the role of ZEB1 acetylation in regulating function, we generated ZEB1 acetyl-mimetic (K811Q) and acetyl-deficient (K811R) mutant-expressing non-small cell lung cancer cell lines (NSCLC). We demonstrate that the K811R ZEB1 (125 kDa) has a shorter protein half-life than wild-type (WT) ZEB1 and K811Q ZEB1 (∼225 kDa), suggesting that lack of ZEB1 acetylation in the lower molecular weight form affects protein stability. Further, the acetylated form of ZEB1 recruits the nucleosome remodeling and deacetylase (NuRD) complex to bind the promoter of its target genes mir200c-141 and SEMA3F. RNA-sequencing revealed that WT ZEB1 and K811Q ZEB1 downregulate the expression of epithelial genes to promote lung adenocarcinoma invasion and metastasis, whereas the K811R ZEB1 does not. Our findings establish that the K811 acetylation promotes ZEB1 protein stability, interaction with other protein complexes, and subsequent invasion/metastasis of lung adenocarcinoma via epithelial-to-mesenchymal transition. IMPLICATIONS: The molecular mechanisms by which ZEB1 is regulated by K811 acetylation to promote protein stability, NuRD complex and promoter interactions, and function are relevant to the development of treatment strategies to prevent and treat metastasis in patients with NSCLC.


Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Acetilación , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Procesamiento Proteico-Postraduccional , Adenocarcinoma del Pulmón/genética , Transición Epitelial-Mesenquimal/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética
12.
Cell Mol Life Sci ; 68(8): 1439-54, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20859650

RESUMEN

A decrease in the levels of the desmosomal plaque protein, plakophilin3 (PKP3), leads to a decrease in desmosome size and cell-cell adhesion. To test the hypothesis that PKP3 is required for desmosome formation, the recruitment of desmosomal components to the cell surface was studied in the PKP3 knockdown clones. The PKP3 knockdown clones showed decreased cell border staining for multiple desmosomal proteins, when compared to vector controls, and did not form desmosomes in a calcium switch assay. Further analysis demonstrated that PKP3, plakoglobin (PG) and E-cadherin are present at the cell border at low concentrations of calcium. Loss of either PG or E-cadherin led to a decrease in the levels of PKP3 and other desmosomal proteins at the cell border. The results reported here are consistent with the model that PG and E-cadherin recruit PKP3 to the cell border to initiate desmosome formation.


Asunto(s)
Cadherinas/metabolismo , Desmosomas/metabolismo , Placofilinas/metabolismo , gamma Catenina/metabolismo , Adhesión Celular , Línea Celular , Técnica del Anticuerpo Fluorescente , Técnicas de Silenciamiento del Gen , Células HCT116 , Células HEK293 , Humanos , Microscopía Confocal , Placofilinas/genética
13.
Org Lett ; 24(49): 9001-9006, 2022 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-36469513

RESUMEN

Benzoperylenocarbazole (BPC), a unique carbazole-based organophotocatalyst, is reported herein as a potent organo-photoreductant. Lower excited state oxidation potential (-2.0 V vs SCE) and reasonable excited state lifetime (4.61 ns) render BPC an effective photosensitizer. Under irradiation of blue light employing low catalyst loading (0.5 mol %), a plethora of vicinal diols and diamines were synthesized in excellent yields through reductive coupling of carbonyls and imines, respectively. Insight about the electronic structure of BPC was obtained by DFT calculations.

14.
Cell Rep ; 40(13): 111429, 2022 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-36170810

RESUMEN

Lung cancer is a highly aggressive and metastatic disease responsible for approximately 25% of all cancer-related deaths in the United States. Using high-throughput in vitro and in vivo screens, we have previously established Impad1 as a driver of lung cancer invasion and metastasis. Here we elucidate that Impad1 is a direct target of the epithelial microRNAs (miRNAs) miR-200 and miR∼96 and is de-repressed during epithelial-to-mesenchymal transition (EMT); thus, we establish a mode of regulation of the protein. Impad1 modulates Golgi apparatus morphology and vesicular trafficking through its interaction with a trafficking protein, Syt11. These changes in Golgi apparatus dynamics alter the extracellular matrix and the tumor microenvironment (TME) to promote invasion and metastasis. Inhibiting Impad1 or Syt11 disrupts the cancer cell secretome, regulates the TME, and reverses the invasive or metastatic phenotype. This work identifies Impad1 as a regulator of EMT and secretome-mediated changes during lung cancer progression.


Asunto(s)
Neoplasias Pulmonares , MicroARNs , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , Invasividad Neoplásica/genética , Metástasis de la Neoplasia , Sinaptotagminas/metabolismo , Microambiente Tumoral
15.
Chem Commun (Camb) ; 57(47): 5762-5765, 2021 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-34008629

RESUMEN

A Brønsted acid catalyzed cascade benzannulation strategy for the one-pot synthesis of densely populated poly-aryl benzo[a]carbazole architectures is disclosed from easily affordable fundamental commodities. The efficacy of this technique was further validated via the concise synthesis of structurally unique carbazole based poly-aromatic hydrocarbons. Furthermore, the photo-physical properties of the synthesized compounds are thoroughly investigated.

16.
bioRxiv ; 2021 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-32577652

RESUMEN

COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. We find that ACE2 expression is restricted to a select population of highly epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium, induces metabolic and transcriptional changes consistent with epithelial to mesenchymal transition (EMT), including upregulation of ZEB1 and AXL, resulting in an increased EMT score. Additionally, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT via TGFbeta, ZEB1 overexpression and onset of EGFR TKI inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect. These observations highlight the utility of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses, and offer important insights into the potential mechanisms underlying the morbidity and mortality of COVID-19 in healthy patients and cancer patients alike.

17.
J Thorac Oncol ; 16(11): 1821-1839, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34274504

RESUMEN

INTRODUCTION: Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells through the cell surface proteins ACE2 and TMPRSS2. METHODS: Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. RESULTS: We find that ACE2 expression is restricted to a select population of epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium induces metabolic and transcriptional changes consistent with epithelial-to-mesenchymal transition (EMT), including up-regulation of ZEB1 and AXL, resulting in an increased EMT score. In addition, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT through the transforming growth factor-ß, ZEB1 overexpression, and onset of EGFR tyrosine kinase inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL inhibition and ZEB1 reduction, as with bemcentinib, offer a potential strategy to reverse this effect. CONCLUSIONS: These observations highlight the use of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses and offer important insights into the potential mechanisms underlying the morbidity and mortality of coronavirus disease 2019 in healthy patients and patients with cancer alike.


Asunto(s)
COVID-19 , Neoplasias Pulmonares , Bronquios , Humanos , Pulmón , Peptidil-Dipeptidasa A , SARS-CoV-2
18.
Exp Cell Res ; 315(8): 1448-57, 2009 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-19331823

RESUMEN

Mitotic progression requires the activity of the dual specificity phosphatase, cdc25C. Cdc25C function is inhibited by complex formation with two 14-3-3 isoforms, 14-3-3epsilon and 14-3-3gamma. To understand the molecular basis of specific complex formation between 14-3-3 proteins and their ligands, chimeric 14-3-3 proteins were tested for their ability to form a complex with cdc25C in vivo. Specific complex formation between cdc25C and 14-3-3epsilon in vivo requires a phenylalanine residue at position 135 (F135) in 14-3-3epsilon. Mutation of this residue to the corresponding residue present in other 14-3-3 isoforms (F135V) leads to reduced binding to cdc25C and a decrease in the ability to inhibit cdc25C function in vivo. Similarly, F135V failed to rescue the incomplete S phase and the G2 DNA damage checkpoint defects observed in cells lacking 14-3-3epsilon. A comparative analysis of the 14-3-3 structures present in the database suggested that the F135 in 14-3-3epsilon was required to maintain the integrity of a pocket that might be involved in secondary interactions with cdc25C. These results suggest that the specificity of the 14-3-3 ligand interaction may be dependent on structural motifs present in the individual 14-3-3 isoforms.


Asunto(s)
Proteínas 14-3-3/genética , Proteínas de Ciclo Celular/metabolismo , Fosfatasas cdc25/metabolismo , Proteínas 14-3-3/química , Proteínas 14-3-3/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Humanos , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Filogenia , Unión Proteica , Estructura Terciaria de Proteína , Ratas , Alineación de Secuencia , Transducción de Señal
19.
Oncogene ; 39(43): 6719-6732, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32963352

RESUMEN

Metastasis is the cause for 90% of cancer-related mortalities. Identification of genetic drivers promoting dissemination of tumor cells may provide opportunities for novel therapeutic strategies. We previously reported an in vivo gain-of-function screen that identified ~30 genes with a functional role in metastasis promotion and characterized detailed mechanistic functions of two hits. In this study, we characterized the contribution of one of the identified genes, MBIP (MAP3K12 binding inhibitory protein), towards driving tumor invasion and metastasis. We demonstrate that expression of MBIP significantly enhances the cellular proliferation, migration and invasion of NSCLC cells in vitro and metastasis in vivo. We functionally characterized that MBIP mediates activation of the JNK pathway and induces expression of matrix metalloproteinases (MMPs), which are necessary for the invasive and metastatic phenotype. Our findings establish a novel mechanistic role of MBIP as a driver of NSCLC progression and metastasis.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Pulmonares/patología , Metaloproteinasas de la Matriz/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/secundario , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Mutación con Ganancia de Función , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/genética , Masculino , Ratones , Invasividad Neoplásica/genética , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Oncogene ; 39(37): 5979-5994, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32753652

RESUMEN

Non-small cell lung cancer (NSCLC) is the deadliest form of cancer worldwide, due in part to its proclivity to metastasize. Identifying novel drivers of invasion and metastasis holds therapeutic potential for the disease. We conducted a gain-of-function invasion screen, which identified two separate hits, IMPAD1 and KDELR2, as robust, independent drivers of lung cancer invasion and metastasis. Given that IMPAD1 and KDELR2 are known to be localized to the ER-Golgi pathway, we studied their common mechanism of driving in vitro invasion and in vivo metastasis and demonstrated that they enhance Golgi-mediated function and secretion. Therapeutically inhibiting matrix metalloproteases (MMPs) suppressed both IMPAD1- and KDELR2-mediated invasion. The hits from this unbiased screen and the mechanistic validation highlight Golgi function as one of the key cellular features altered during invasion and metastasis.


Asunto(s)
Aparato de Golgi/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Monoéster Fosfórico Hidrolasas/genética , Proteínas de Transporte Vesicular/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Metaloproteinasas de la Matriz/metabolismo , Invasividad Neoplásica , Monoéster Fosfórico Hidrolasas/metabolismo , Proteínas de Transporte Vesicular/metabolismo
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