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1.
Proc Natl Acad Sci U S A ; 118(31)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34330832

RESUMO

UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models. We found that transcription of UGP2 is directly regulated by the Yes-associated protein 1 (YAP)-TEA domain transcription factor (TEAD) complex, identifying UGP2 as a bona fide YAP target gene. Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs.


Assuntos
Carcinoma Ductal Pancreático/enzimologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Glicogênio/biossíntese , Neoplasias Pancreáticas/enzimologia , UTP-Glucose-1-Fosfato Uridililtransferase/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Glicosilação , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais , Neoplasias Pancreáticas/patologia , Fatores de Transcrição de Domínio TEA/genética , Fatores de Transcrição de Domínio TEA/metabolismo , UTP-Glucose-1-Fosfato Uridililtransferase/genética , Proteínas de Sinalização YAP/genética , Proteínas de Sinalização YAP/metabolismo
2.
PLoS Genet ; 10(10): e1004592, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25340400

RESUMO

In addition to their protein coding function, exons can also serve as transcriptional enhancers. Mutations in these exonic-enhancers (eExons) could alter both protein function and transcription. However, the functional consequence of eExon mutations is not well known. Here, using massively parallel reporter assays, we dissect the enhancer activity of three liver eExons (SORL1 exon 17, TRAF3IP2 exon 2, PPARG exon 6) at single nucleotide resolution in the mouse liver. We find that both synonymous and non-synonymous mutations have similar effects on enhancer activity and many of the deleterious mutation clusters overlap known liver-associated transcription factor binding sites. Carrying a similar massively parallel reporter assay in HeLa cells with these three eExons found differences in their mutation profiles compared to the liver, suggesting that enhancers could have distinct operating profiles in different tissues. Our results demonstrate that eExon mutations could lead to multiple phenotypes by disrupting both the protein sequence and enhancer activity and that enhancers can have distinct mutation profiles in different cell types.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Elementos Facilitadores Genéticos , Éxons/genética , Proteínas de Membrana Transportadoras/genética , PPAR gama/genética , Receptores de LDL/genética , Animais , Sítios de Ligação , Regulação da Expressão Gênica , Células HeLa , Humanos , Fígado/metabolismo , Camundongos , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Splicing de RNA/genética , Fatores de Transcrição/biossíntese
3.
Metabolites ; 12(9)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36144235

RESUMO

Cancer cells utilize multiple nutrient scavenging mechanisms to support growth and survival in nutrient-poor, hypoxic tumor microenvironments. Among these mechanisms, macropinocytosis has emerged as an important pathway of extracellular nutrient acquisition in cancer cells, particularly in tumors with activated RAS signaling, such as pancreatic cancer. However, the absence of a clinically available inhibitor, as well as the gap of knowledge in macropinocytosis regulation, remain a hurdle for its use for cancer therapy. Here, we use the Informer set library to identify novel regulators of macropinocytosis-dependent growth in pancreatic cancer cells. Understanding how these regulators function will allow us to provide novel opportunities for therapeutic intervention.

4.
Nat Commun ; 11(1): 2375, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398776

RESUMO

Synthetic lethal screens have the potential to identify new vulnerabilities incurred by specific cancer mutations but have been hindered by lack of agreement between studies. In the case of KRAS, we identify that published synthetic lethal screen hits significantly overlap at the pathway rather than gene level. Analysis of pathways encoded as protein networks could identify synthetic lethal candidates that are more reproducible than those previously reported. Lack of overlap likely stems from biological rather than technical limitations as most synthetic lethal phenotypes are strongly modulated by changes in cellular conditions or genetic context, the latter determined using a pairwise genetic interaction map that identifies numerous interactions that suppress synthetic lethal effects. Accounting for pathway, cellular and genetic context nominates a DNA repair dependency in KRAS-mutant cells, mediated by a network containing BRCA1. We provide evidence for why most reported synthetic lethals are not reproducible which is addressable using a multi-faceted testing framework.


Assuntos
Biologia Computacional/métodos , Análise de Dados , Redes Reguladoras de Genes , Neoplasias/genética , Mutações Sintéticas Letais , Animais , Proteína BRCA1/genética , Linhagem Celular Tumoral , Biologia Computacional/normas , Modelos Animais de Doenças , Humanos , Camundongos , Mapas de Interação de Proteínas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Reprodutibilidade dos Testes
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