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1.
Nature ; 535(7611): 246-51, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27383785

RESUMO

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.


Assuntos
Amplificação de Genes/genética , MicroRNAs/genética , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Proteínas de Ligação a RNA/genética , Regiões 3' não Traduzidas/genética , Animais , Deleção Cromossômica , Feminino , Deleção de Genes , Genes Neoplásicos/genética , Humanos , Camundongos , MicroRNAs/metabolismo , Modelos Genéticos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Proc Natl Acad Sci U S A ; 110(16): 6524-9, 2013 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-23553831

RESUMO

Small-cell lung cancer and other aggressive neuroendocrine cancers are often associated with early dissemination and frequent metastases. We demonstrate that neurogenic differentiation 1 (NeuroD1) is a regulatory hub securing cross talk among survival and migratory-inducing signaling pathways in neuroendocrine lung carcinomas. We find that NeuroD1 promotes tumor cell survival and metastasis in aggressive neuroendocrine lung tumors through regulation of the receptor tyrosine kinase tropomyosin-related kinase B (TrkB). Like TrkB, the prometastatic signaling molecule neural cell adhesion molecule (NCAM) is a downstream target of NeuroD1, whose impaired expression mirrors loss of NeuroD1. TrkB and NCAM may be therapeutic targets for aggressive neuroendocrine cancers that express NeuroD1.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Neoplasias Pulmonares/fisiopatologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Receptor trkB/metabolismo , Carcinoma de Pequenas Células do Pulmão/fisiopatologia , Análise de Variância , Animais , Carbazóis , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Primers do DNA/genética , Furanos , Humanos , Immunoblotting , Imunoprecipitação , Luciferases , Neoplasias Pulmonares/metabolismo , Camundongos , Análise em Microsséries , Plasmídeos/genética , Reação em Cadeia da Polimerase em Tempo Real , Carcinoma de Pequenas Células do Pulmão/metabolismo
3.
Proc Natl Acad Sci U S A ; 108(51): 20713-8, 2011 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-22143803

RESUMO

New drugs for preserving and restoring pancreatic ß-cell function are critically needed for the worldwide epidemic of type 2 diabetes and the cure for type 1 diabetes. We previously identified a family of neurogenic 3,5-disubstituted isoxazoles (Isx) that increased expression of neurogenic differentiation 1 (NeuroD1, also known as BETA2); this transcription factor functions in neuronal and pancreatic ß-cell differentiation and is essential for insulin gene transcription. Here, we probed effects of Isx on human cadaveric islets and MIN6 pancreatic ß cells. Isx increased the expression and secretion of insulin in islets that made little insulin after prolonged ex vivo culture and increased expression of neurogenic differentiation 1 and other regulators of islet differentiation and insulin gene transcription. Within the first few hours of exposure, Isx caused biphasic activation of ERK1/2 and increased bulk histone acetylation. Although there was little effect on histone deacetylase activity, Isx increased histone acetyl transferase activity in nuclear extracts. Reconstitution assays indicated that Isx increased the activity of the histone acetyl transferase p300 through an ERK1/2-dependent mechanism. In summary, we have identified a small molecule with antidiabetic activity, providing a tool for exploring islet function and a possible lead for therapeutic intervention in diabetes.


Assuntos
Células Secretoras de Insulina/citologia , Insulina/metabolismo , Isoxazóis/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Núcleo Celular/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Células HEK293 , Humanos , Ilhotas Pancreáticas/metabolismo , Camundongos , Neurônios/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
4.
Cancers (Basel) ; 15(23)2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-38067222

RESUMO

Cellular locomotion is required for survival, fertility, proper embryonic development, regeneration, and wound healing. Cell migration is a major component of metastasis, which accounts for two-thirds of all solid tumor deaths. While many studies have demonstrated increased energy requirements, metabolic rates, and migration of cancer cells compared with normal cells, few have systematically compared normal and cancer cell migration as well as energy requirements side by side. Thus, we investigated how non-malignant and malignant cells migrate, utilizing several cell lines from the breast and lung. Initial screening was performed in an unbiased high-throughput manner for the ability to migrate/invade on collagen and/or Matrigel. We unexpectedly observed that all the non-malignant lung cells moved significantly faster than cells derived from lung tumors regardless of the growth media used. Given the paradigm-shifting nature of our discovery, we pursued the mechanisms that could be responsible. Neither mass, cell doubling, nor volume accounted for the individual speed and track length of the normal cells. Non-malignant cells had higher levels of intracellular ATP at premigratory-wound induction stages. Meanwhile, cancer cells also increased intracellular ATP at premigratory-wound induction, but not to the levels of the normal cells, indicating the possibility for further therapeutic investigation.

5.
Cancer Res ; 82(6): 972-973, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35288734

RESUMO

Identifying the cell(s) of origin for lung cancer including detecting their expansion during "field cancerization" and understanding how to therapeutically target them for beneficial chemoprevention is an urgent need. In this issue of Cancer Research, Yin and colleagues provide new and potentially controversial information to this question using Gprc5a knockout genetically engineered mouse models of lung adenocarcinoma. Prior research identified several different cell types including resident lung stem/progenitor such as alveolar type II cells as well as terminally differentiated cells as candidates for the cancer-initiating cell. Yin and colleagues provide new information that the cancer-initiating cell in this model is the bronchioalveolar stem cell. See related article by Yin et al., p. 1025.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Animais , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Receptores Acoplados a Proteínas G , Células-Tronco/metabolismo
6.
Cell Rep ; 36(3): 109408, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34289374

RESUMO

The molecular mechanisms that govern the choreographed timing of organ development remain poorly understood. Our investigation of the role of the Lin28a and Lin28b paralogs during the developmental process of branching morphogenesis establishes that dysregulation of Lin28a/b leads to abnormal branching morphogenesis in the lung and other tissues. Additionally, we find that the Lin28 paralogs, which regulate post-transcriptional processing of both mRNAs and microRNAs (miRNAs), predominantly control mRNAs during the initial phases of lung organogenesis. Target mRNAs include Sox2, Sox9, and Etv5, which coordinate lung development and differentiation. Moreover, we find that functional interactions between Lin28a and Sox9 are capable of bypassing branching defects in Lin28a/b mutant lungs. Here, we identify Lin28a and Lin28b as regulators of early embryonic lung development, highlighting the importance of the timing of post-transcriptional regulation of both miRNAs and mRNAs at distinct stages of organogenesis.


Assuntos
Pulmão/embriologia , Pulmão/metabolismo , Morfogênese , Proteínas de Ligação a RNA/metabolismo , Homologia de Sequência de Aminoácidos , Embrião de Mamíferos/metabolismo , Retroalimentação Fisiológica , Fator 10 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Morfogênese/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/genética
7.
Cell Stem Cell ; 27(4): 499-500, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007229

RESUMO

Discovered as a proto-oncogene 40 years ago, mutations in KRAS exist in ∼30% of all human cancers. In this issue of Cell Stem Cell,Dost et al. (2020) combine the power of analyzing organoid cultures, patient samples, and mouse models with scRNA-seq to elucidate early events occurring with oncogenic KRAS activation.


Assuntos
Proteínas Proto-Oncogênicas , Proteínas ras , Humanos , Pulmão/metabolismo , Mutação/genética , Organoides/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Células-Tronco/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
8.
Nat Commun ; 11(1): 1327, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152305

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

9.
Nat Commun ; 10(1): 168, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635573

RESUMO

In humans and in mice the formation of nephrons during embryonic development reaches completion near the end of gestation, after which no new nephrons are formed. The final nephron complement can vary 10-fold, with reduced nephron number predisposing individuals to hypertension, renal, and cardiovascular diseases in later life. While the heterochronic genes lin28 and let-7 are well-established regulators of developmental timing in invertebrates, their role in mammalian organogenesis is not fully understood. Here we report that the Lin28b/let-7 axis controls the duration of kidney development in mice. Suppression of let-7 miRNAs, directly or via the transient overexpression of LIN28B, can prolong nephrogenesis and enhance kidney function potentially via upregulation of the Igf2/H19 locus. In contrast, kidney-specific loss of Lin28b impairs renal development. Our study reveals mechanisms regulating persistence of nephrogenic mesenchyme and provides a rationale for therapies aimed at increasing nephron mass.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Rim/embriologia , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Feminino , Fator de Crescimento Insulin-Like II/metabolismo , Rim/metabolismo , Testes de Função Renal , Masculino , Camundongos Transgênicos , RNA Longo não Codificante/metabolismo
10.
Nat Cell Biol ; 19(1): 60-67, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27992407

RESUMO

Signalling and post-transcriptional gene control are both critical for the regulation of pluripotency, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein, has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA biogenesis and direct modulation of mRNA translation. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells, which increases its levels via post-translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced the effect of LIN28 on its direct mRNA targets, revealing a mechanism that uncouples LIN28's let-7-dependent and -independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naive to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signalling, post-transcriptional gene control, and cell fate regulation.


Assuntos
Sistema de Sinalização das MAP Quinases , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transcrição Gênica , Sequência de Aminoácidos , Animais , Western Blotting , Células HeLa , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , MicroRNAs/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Fosforilação , Domínios Proteicos , Estabilidade Proteica
11.
Aging Cell ; 4(4): 197-207, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16026334

RESUMO

The identification of neural stem cells (NSCs) in situ has been prevented by the inability to identify a marker consistently expressed in all adult NSCs and is thus generally accomplished using the in vitro neurosphere-forming assay. The high-mobility group transcription factor Sox2 is expressed in embryonic neural epithelial stem cells; because these cells are thought to give rise to the adult NSC population, we hypothesized that Sox2 may continue to be expressed in adult NSCs. Using Sox2:EGFP transgenic mice, we show that Sox2 is expressed in neurogenic regions along the rostral-caudal axis of the central nervous system throughout life. Furthermore, all neurospheres derived from these neurogenic regions express Sox2, suggesting that Sox2 is indeed expressed in adult NSCs. We demonstrate that NSCs are heterogeneous within the adult brain, with differing capacities for cell production. In vitro, all neurospheres express Sox2, but the expression of markers common to early progenitor cells within individual neurospheres varies; this heterogeneity of NSCs is mirrored in vivo. For example, both glial fibrillary acidic protein and NG2 are expressed within individual neurospheres, but their expression is mutually exclusive; likewise, these two markers show distinct staining patterns within the Sox2+ regions of the brain's neurogenic regions. Thus, we propose that the expression of Sox2 is a unifying characteristic of NSCs in the adult brain, but that not all NSCs maintain the ability to form all neural cell types in vivo.


Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a DNA/biossíntese , Proteínas HMGB/biossíntese , Neurônios/metabolismo , Células-Tronco/metabolismo , Fatores de Transcrição/biossíntese , Fatores Etários , Animais , Encéfalo/citologia , Diferenciação Celular/fisiologia , Células Cultivadas , DNA Complementar/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Proteínas HMGB/genética , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXB1 , Células-Tronco/citologia , Telomerase/metabolismo , Fatores de Transcrição/genética
12.
Cell Rep ; 16(5): 1259-1272, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27452466

RESUMO

Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Células Neuroendócrinas/metabolismo , Oncogenes/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
J Clin Invest ; 126(9): 3219-35, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27500490

RESUMO

Increased expression of zinc finger E-box binding homeobox 1 (ZEB1) is associated with tumor grade and metastasis in lung cancer, likely due to its role as a transcription factor in epithelial-to-mesenchymal transition (EMT). Here, we modeled malignant transformation in human bronchial epithelial cells (HBECs) and determined that EMT and ZEB1 expression are early, critical events in lung cancer pathogenesis. Specific oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGF-ß) or oncogenetic (MYC) factors. Both TGF-ß- and MYC-induced EMT required ZEB1, but engaged distinct TGF-ß-dependent and vitamin D receptor-dependent (VDR-dependent) pathways, respectively. Functionally, we found that ZEB1 causally promotes malignant progression of HBECs and tumorigenicity, invasion, and metastases in non-small cell lung cancer (NSCLC) lines. Mechanistically, ZEB1 expression in HBECs directly repressed epithelial splicing regulatory protein 1 (ESRP1), leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype. In addition, ZEB1 expression in early stage IB primary NSCLC correlated with tumor-node-metastasis stage. These findings indicate that ZEB1-induced EMT and associated molecular changes in ESRP1 and CD44 contribute to early pathogenesis and metastatic potential in established lung cancer. Moreover, TGF-ß and VDR signaling and CD44 splicing pathways associated with ZEB1 are potential EMT chemoprevention and therapeutic targets in NSCLC.


Assuntos
Transição Epitelial-Mesenquimal , Receptores de Hialuronatos/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/metabolismo , Linhagem Celular , Transformação Celular Neoplásica , Feminino , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microcirculação , Invasividade Neoplásica , Metástase Neoplásica , Fenótipo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Calcitriol/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
14.
Mol Biol Cell ; 25(11): 1782-92, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24719457

RESUMO

Cigarette smoking is a major risk factor for acquisition of small cell lung cancer (SCLC). A role has been demonstrated for the basic helix-loop-helix transcription factor NeuroD1 in the pathogenesis of neural and neuroendocrine lung cancer, including SCLC. In the present study we investigate the possible function of NeuroD1 in established tumors, as well as actions early on in pathogenesis, in response to nicotine. We demonstrate that nicotine up-regulates NeuroD1 in immortalized normal bronchial epithelial cells and a subset of undifferentiated carcinomas. Increased expression of NeuroD1 subsequently leads to regulation of expression and function of the nicotinic acetylcholine receptor subunit cluster of α3, α5, and ß4. In addition, we find that coordinated expression of these subunits by NeuroD1 leads to enhanced nicotine-induced migration and invasion, likely through changes in intracellular calcium. These findings suggest that aspects of the pathogenesis of neural and neuroendocrine lung cancers may be affected by a nicotine- and NeuroD1-induced positive feedback loop.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Movimento Celular/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Nicotina/farmacologia , Subunidades Proteicas/metabolismo , Receptores Nicotínicos/metabolismo , Brônquios/patologia , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Clonais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Modelos Biológicos , Mutação , Invasividade Neoplásica , Receptor trkB/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos
15.
Cell Res ; 22(1): 14-22, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22143568

RESUMO

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the prototype mammalian mitogen-activated protein kinase (MAPK) signaling cascade that regulates a number of processes, including proliferation, differentiation, survival, migration, stress responses and apoptosis. How this seemingly linear cascade is modulated to achieve a specific cellular function has been a main focus of the field. In this review, we describe new as well as old findings in the regulation of the ERK1/2 pathway in normal and disease states via MAP3Ks.


Assuntos
Proliferação de Células , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas B-raf/metabolismo , Animais , Calcineurina/metabolismo , Inibidores de Calcineurina , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Ativação Enzimática , Retroalimentação Fisiológica , Glucose/metabolismo , Humanos , Mamíferos , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo
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