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1.
Genes Dev ; 33(17-18): 1252-1264, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31395740

RESUMO

Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of Max has a modest effect on B-cell development but completely abrogates Eµ-Myc-driven lymphomagenesis. While Max loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of Myc-activated genes in premalignant Eµ-Myc cells. We show that the balance between MYC-MAX and MNT-MAX interactions in B cells shifts in premalignant B cells toward a MYC-driven transcriptional program. Moreover, we found that MAX loss leads to a significant reduction in MYC protein levels and down-regulation of direct transcriptional targets, including regulators of MYC stability. This phenomenon is also observed in multiple cell lines treated with MYC-MAX dimerization inhibitors. Our work uncovers a layer of Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal development.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Linfoma/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Deleção de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/farmacologia , Cinurenina/genética , Cinurenina/metabolismo , Linfoma/fisiopatologia , Camundongos , Organoides/crescimento & desenvolvimento , Organoides/fisiopatologia , Oximas/farmacologia , Sulfonamidas/farmacologia
2.
Front Med ; 12(4): 412-425, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30054853

RESUMO

Transcription factor networks have evolved in order to control, coordinate, and separate, the functions of distinct network modules spatially and temporally. In this review we focus on the MYC network (also known as the MAX-MLX Network), a highly conserved super-family of related basic-helix-loop-helix-zipper (bHLHZ) proteins that functions to integrate extracellular and intracellular signals and modulate global gene expression. Importantly the MYC network has been shown to be deeply involved in a broad spectrum of human and other animal cancers. Here we summarize molecular and biological properties of the network modules with emphasis on functional interactions among network members. We suggest that these network interactions serve to modulate growth and metabolism at the transcriptional level in order to balance nutrient demand with supply, to maintain growth homeostasis, and to influence cell fate. Moreover, oncogenic activation of MYC and/or loss of a MYC antagonist, results in an imbalance in the activity of the network as a whole, leading to tumor initiation, progression and maintenance.


Assuntos
Carcinogênese/metabolismo , Redes Reguladoras de Genes/fisiologia , Domínios e Motivos de Interação entre Proteínas/fisiologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Progressão da Doença , Regulação da Expressão Gênica , Humanos
3.
Dev Cell ; 45(6): 738-752.e6, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29920278

RESUMO

Normal cells acquire aggressive behavior by modifying signaling pathways. For instance, alteration of endocytosis profoundly impacts both proliferation and migration during tumorigenesis. Here we investigate the mechanisms that enable the endocytic machinery to coordinate these processes. We show that a membrane curvature-sensing protein, endophilin A3, promotes growth and migration of colon cancer cells through two competing mechanisms: an endocytosis pathway that is required for proliferation and a GTPase regulatory pathway that controls cell motility. EndoA3 stimulates cell migration by binding the Rac GEF TIAM1 leading to activation of small GTPases. Competing interactions of EndoA3 with membrane versus TIAM1 modulate hyperproliferative and metastatic phenotypes. Disruption of EndoA3-membrane interactions stimulates TIAM1 and small GTPases in vitro, and further promotes pro-metastatic phenotypes in vivo. Together, these results uncover a coupling mechanism, by which EndoA3 promotes growth and migration of colon cancers, by linking membrane dynamics to GTPase regulation.


Assuntos
Aciltransferases/metabolismo , Neoplasias do Colo/metabolismo , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transformação Celular Neoplásica , Neoplasias do Colo/patologia , Endocitose/fisiologia , GTP Fosfo-Hidrolases/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Camundongos , Metástase Neoplásica , Transdução de Sinais , Peixe-Zebra , Proteínas rac1 de Ligação ao GTP/metabolismo
4.
Cancer Cell ; 29(1): 1-2, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26766585

RESUMO

Myc and its paralog MycN are thought to be functionally redundant, but Myc- and MycN-driven medulloblastomas exhibit distinct phenotypes. In this issue of Cancer Cell, Vo and colleagues (2016) show that this phenotypic difference stems from the preferential ability of Myc, relative to MycN, to bind Miz1 and repress transcription.


Assuntos
Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Meduloblastoma/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais
5.
Mol Cancer Ther ; 14(1): 307-14, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25376607

RESUMO

The 2-year survival rate of patients with breast cancer brain metastases is less than 2%. Treatment options for breast cancer brain metastases are limited, and there is an unmet need to identify novel therapies for this disease. Brain angiogenesis inhibitor 1 (BAI1) is a GPCR involved in tumor angiogenesis, invasion, phagocytosis, and synaptogenesis. For the first time, we identify that BAI1 expression is significantly reduced in breast cancer and higher expression is associated with better patient survival. Nestin is an intermediate filament whose expression is upregulated in several cancers. We found that higher Nestin expression significantly correlated with breast cancer lung and brain metastases, suggesting both BAI1 and Nestin can be therapeutic targets for this disease. Here, we demonstrate the ability of an oncolytic virus, 34.5ENVE, to target and kill high Nestin-expressing cells and deliver Vstat120 (extracellular fragment of BAI1). Finally, we created two orthotopic immune-competent murine models of breast cancer brain metastases and demonstrated 34.5ENVE extended the survival of immune-competent mice bearing intracranial breast cancer tumors.


Assuntos
Proteínas Angiogênicas/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Nestina/metabolismo , Vírus Oncolíticos/genética , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Metástase Neoplásica , Terapia Viral Oncolítica , Prognóstico , Receptores Acoplados a Proteínas-G , Células Vero
6.
Mol Ther ; 21(8): 1517-25, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23732993

RESUMO

Saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles are a nanotherapeutic which effectively target and destroy cancer cells. Here, we explore the systemic use of SapC-DOPS in several models of brain cancer, including glioblastoma multiforme (GBM), and the molecular mechanism behind its tumor-selective targeting specificity. Using two validated spontaneous brain tumor models, we demonstrate the ability of SapC-DOPS to selectively and effectively cross the blood-brain tumor barrier (BBTB) to target brain tumors in vivo and reveal the targeting to be contingent on the exposure of the anionic phospholipid phosphatidylserine (PtdSer). Increased cell surface expression of PtdSer levels was found to correlate with SapC-DOPS-induced killing efficacy, and tumor targeting in vivo was inhibited by blocking PtdSer exposed on cells. Apart from cancer cell killing, SapC-DOPS also exerted a strong antiangiogenic activity in vitro and in vivo. Interestingly, unlike traditional chemotherapy, hypoxic cells were sensitized to SapC-DOPS-mediated killing. This study emphasizes the importance of PtdSer exposure for SapC-DOPS targeting and supports the further development of SapC-DOPS as a novel antitumor and antiangiogenic agent for brain tumors.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Nanopartículas/administração & dosagem , Fosfatidilserinas/química , Saposinas/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Modelos Animais de Doenças , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Nanopartículas/química , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Saposinas/administração & dosagem , Saposinas/química , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nat Cell Biol ; 14(11): 1122-3, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23131919

RESUMO

Epithelial to mesenchymal transition (EMT) is a fundamental process in both development and cancer progression. The transcription factor Elf5 is now reported as an upstream regulator of the key EMT inducer Snail2, and is shown to regulate the earliest known rewiring events required for tumour cell invasiveness and metastasis.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Neoplasias/metabolismo , Fatores de Transcrição/metabolismo , Animais , Transição Epitelial-Mesenquimal/genética , Humanos , Modelos Biológicos , Metástase Neoplásica/genética , Metástase Neoplásica/fisiopatologia , Neoplasias/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética
8.
Mol Cancer Res ; 9(8): 1091-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21673012

RESUMO

To find genes and proteins that collaborate with BRCA1 or BRCA2 in the pathogenesis of breast cancer, we used an informatics approach and found a candidate BRCA interactor, KIAA0101, to function like BRCA1 in exerting a powerful control over centrosome number. The effect of KIAA0101 on centrosomes is likely direct, as its depletion does not affect the cell cycle, KIAA0101 localizes to regions coincident with the centrosomes, and KIAA0101 binds to BRCA1. We analyzed whether KIAA0101 protein is overexpressed in breast cancer tumor samples in tissue microarrays, and we found that overexpression of KIAA0101 correlated with positive Ki67 staining, a biomarker associated with increased disease severity. Furthermore, overexpression of the KIAA0101 gene in breast tumors was found to be associated with significantly decreased survival time. This study identifies KIAA0101 as a protein important for breast tumorigenesis, and as this factor has been reported as a UV repair factor, it may link the UV damage response to centrosome control.


Assuntos
Proteína BRCA1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Centrossomo/metabolismo , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Dano ao DNA , Proteínas de Ligação a DNA , Proteínas da Matriz Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Células HeLa , Recombinação Homóloga/genética , Humanos , Receptores de Hialuronatos/metabolismo , Antígeno Ki-67/análise , RNA Interferente Pequeno/genética
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