Abstract:
:Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. Protein Tyrosine Phosphatase N23 (PTPN23) resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breast cancer patients. In a loss-of-function PTPome screen, our laboratory identified PTPN23 as a suppressor of cell motility and invasion in mammary epithelial and breast cancer cells. Now, our TCGA (The Cancer Genome Atlas) database analyses illustrate a correlation between low PTPN23 expression and poor survival in breast cancers of various subtypes. Therefore, we investigated the tumor-suppressive function of PTPN23 in an orthotopic transplantation mouse model. Suppression of PTPN23 in Comma 1Dβ cells induced breast tumors within 56 wk. In PTPN23-depleted tumors, we detected hyperphosphorylation of the autophosphorylation site tyrosine in the SRC family kinase (SFK) FYN as well as Tyr142 in β-catenin. We validated the underlying mechanism of PTPN23 function in breast tumorigenesis as that of a key phosphatase that normally suppresses the activity of FYN in two different models. We demonstrated that tumor outgrowth from PTPN23-deficient BT474 cells was suppressed in a xenograft model in vivo upon treatment with AZD0530, an SFK inhibitor. Furthermore, double knockout of FYN and PTPN23 via CRISPR/CAS9 also attenuated tumor outgrowth from PTPN23 knockout Cal51 cells. Overall, this mechanistic analysis of the tumor-suppressive function of PTPN23 in breast cancer supports the identification of FYN as a therapeutic target for breast tumors with heterozygous or homozygous loss of PTPN23.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Zhang S,Fan G,Hao Y,Hammell M,Wilkinson JE,Tonks NKdoi
10.1101/gad.304261.117subject
Has Abstractpub_date
2017-10-01 00:00:00pages
1939-1957issue
19eissn
0890-9369issn
1549-5477pii
gad.304261.117journal_volume
31pub_type
杂志文章abstract::Cells have evolved checkpoint responses to arrest or delay the cell cycle, activate DNA repair networks, or induce apoptosis after genomic perturbation. Cells have also evolved the translesion synthesis processes to tolerate genomic lesions by either error-free or error-prone repair. Here, we show that after a replica...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1043203
更新日期:2003-01-01 00:00:00
abstract::Two broad gene classes are distinguished within multicellular organisms: cell type-specific genes, which confer particular cellular properties, and ubiquitous genes that support general cellular functions. However, certain so-called ubiquitous genes show functionally relevant cell type-specific repression. How such re...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.287904.116
更新日期:2016-09-15 00:00:00
abstract::The basic helix-loop-helix (bHLH) gene Hes7, a putative Notch effector, encodes a transcriptional repressor. Here, we found that Hes7 expression oscillates in 2-h cycles in the presomitic mesoderm (PSM). In Hes7-null mice, somites are not properly segmented and their anterior-posterior polarity is disrupted. As a resu...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.930601
更新日期:2001-10-15 00:00:00
abstract::The lysosomal storage disorder galactosialidosis results from a primary deficiency of the protective protein/cathepsin A (PPCA), which in turn affects the activities of beta-galactosidase and neuraminidase. Mice homozygous for a null mutation at the PPCA locus present with signs of the disease shortly after birth and ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.21.2623
更新日期:1995-11-01 00:00:00
abstract::The HOP2 and MND1 genes are indispensable for meiotic recombination. The products of these genes associate to form a stable heterodimeric complex that binds DNA and stimulates the recombinase activity of Rad51 and Dmc1. Here we conduct molecular studies to delineate the action mechanism of the Hop2-Mnd1 complex. We pr...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1563007
更新日期:2007-07-15 00:00:00
abstract::Hypocretin (orexin; Hcrt)-containing neurons of the hypothalamus are essential for the normal regulation of sleep and wake behaviors and have been implicated in feeding, anxiety, depression, and reward. The absence of these neurons causes narcolepsy in humans and model organisms. However, little is known about the mol...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.207654.112
更新日期:2013-03-01 00:00:00
abstract::The crucifer Arabidopsis thaliana has been used widely as a model organism for the study of plant development. We describe here the development of an efficient insertional mutagenesis system in Arabidopsis that permits identification of genes by their patterns of expression during development. Transposable elements of...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.14.1797
更新日期:1995-07-15 00:00:00
abstract::Evidence is presented that the activation of the RNA polymerase sigma factor sigma(W) in Bacillus subtilis by regulated intramembrane proteolysis is governed by a novel, membrane-embedded protease. The sigma(W) factor is activated by proteolytic destruction of the membrane-bound anti-sigma(W) factor RsiW in response t...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1440606
更新日期:2006-07-15 00:00:00
abstract::We identify the "M region" of the muscle-specific Xenopus cardiac actin gene promoter from -282 to -348 as necessary for the embryonic expression of a cardiac actin-beta-globin reporter gene injected into fertilized eggs. Four DNA-binding activities in embryo extracts, embryonic M-region factors 1-4 (EMF1-4), are desc...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.5.7.1149
更新日期:1991-07-01 00:00:00
abstract::Alternative splicing factor/splicing factor 2 (ASF/SF2) is the prototype of a family of nuclear proteins highly conserved throughout metazoa, the SR (serine/arginine) proteins. Based largely on in vitro studies, SR proteins have been suggested to play important roles in constitutive and alternative splicing of pre-mRN...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.20.2588
更新日期:1996-10-15 00:00:00
abstract::The nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs). Seven genes (smg-1-7, for suppressor with morphological effect on genitalia) that are essential for NMD were originally identified in the nematode Caenorhabditis elegans, and orthologs of these gene...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.417707
更新日期:2007-05-01 00:00:00
abstract::The discovery of transcription factors (TFs) controlling pathways in health and disease is of paramount interest. We designed a widely applicable method, dubbed barcorded synthetic tandem repeat promoter screening (BC-STAR-PROM), to identify signal-activated TFs without any a priori knowledge about their properties. T...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.284828.116
更新日期:2016-08-15 00:00:00
abstract::Medulloblastomas are among the most common malignancies in childhood, and they are associated with substantial mortality and morbidity. The molecular pathogenesis as well as the ontogeny of these neoplasms is still poorly understood. We have generated a mouse model for medulloblastoma by Cre-LoxP-mediated inactivation...
journal_title:Genes & development
pub_type: 杂志文章
doi:
更新日期:2000-04-15 00:00:00
abstract::The mechanisms by which homeoproteins bind selectively to target genes in vivo have long remained unresolved. Here we report that PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein by regulating its subnuclear localization and proximity to target genes. We demonstrate that the interaction of Msx1 with PIAS...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1392006
更新日期:2006-04-01 00:00:00
abstract::Genomic imprinting is an epigenetic phenomenon leading to parentally biased gene expression. Throughout the years, extensive efforts have been made to characterize the epigenetic marks underlying imprinting in animals and plants. As a result, DNA methylation asymmetries between parental genomes emerged as the primary ...
journal_title:Genes & development
pub_type: 杂志文章,评审
doi:10.1101/gad.332924.119
更新日期:2020-01-01 00:00:00
abstract::The oncoprotein MDM2 binds to the activation domain of the tumor suppressor p53 and inhibits its ability to stimulate transcription. This same region of p53 is able to bind several basal transcription factors that appear to be important for the transactivation function of p53. It has therefore been suggested that MDM2...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.11.15.1974
更新日期:1997-08-01 00:00:00
abstract::Far1p is a bifunctional protein that is required to arrest the cell cycle and to establish cell polarity during yeast mating. Far1p is localized predominantly in the nucleus but accumulates in the cytoplasm in cells exposed to pheromones. Here we show that Far1p functions in both subcellular compartments: nuclear Far1...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.13.17.2284
更新日期:1999-09-01 00:00:00
abstract::The target gene(s) required for Myc-mediated tumorigenesis are still elusive. Here we show that while endogenous c-Myc is surprisingly dispensable for skin homeostasis and TPA-induced hyperplasia, c-Myc-deficient epidermis is resistant to Ras-mediated DMBA/TPAinduced tumorigenesis. This is mechanistically linked to p2...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.381206
更新日期:2006-08-01 00:00:00
abstract::The contact site A glycoprotein is a developmentally regulated cell-surface component expressed during the aggregation stage of Dictyostelium discoideum. This protein has been implicated in the EDTA-stable (Ca2(+)-independent) type of cell adhesion of aggregating cells. The gene coding for the contact site A protein w...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.3.12a.2011
更新日期:1989-12-01 00:00:00
abstract::The current model for endocrine cell specification in the pancreas invokes high-level production of the transcription factor Neurogenin 3 (Neurog3) in Sox9(+) bipotent epithelial cells as the trigger for endocrine commitment, cell cycle exit, and rapid delamination toward proto-islet clusters. This model posits a tran...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.284729.116
更新日期:2016-08-15 00:00:00
abstract::In this issue of Genes & Development, Wierzbicki and colleagues (pp. 1825-1836) examine the current model of RNA-directed DNA methylation (RdDM) by determining genome-wide distributions of RNA polymerase V (Pol V) occupancy, siRNAs, and DNA methylation. Their data support the key role of base-pairing between Pol V tra...
journal_title:Genes & development
pub_type: 评论,杂志文章
doi:10.1101/gad.200410.112
更新日期:2012-08-15 00:00:00
abstract::Nitric oxide (NO) is an important second messenger involved in numerous biological processes, but how it regulates gene expression is not well understood. In this issue of Genes & Development, Cáceres and colleagues (pp. 1476-1485) report a critical requirement of NO as a direct regulator of gene expression through it...
journal_title:Genes & development
pub_type: 评论,杂志文章
doi:10.1101/gad.2080411
更新日期:2011-07-15 00:00:00
abstract::The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prevents closure of a PT pore component, the voltage-dependent anion channel (VDAC); intracellular acidification; mitochondrial hyperpolarization; and the decline in oxidati...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.889901
更新日期:2001-06-01 00:00:00
abstract::Caenorhabditis elegans let-7, a founding member of the microRNA family, is predicted to bind to six sites in the 3'UTR of the mRNA of its target gene, lin-41, to down-regulate LIN-41. Here, we demonstrate that wild-type let-7 microRNA binds in vitro to RNA from the lin-41 3'UTR. This interaction is dependent on two co...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1165404
更新日期:2004-01-15 00:00:00
abstract::Growth of numerous cancer types is believed to be driven by a subpopulation of poorly differentiated cells, often referred to as cancer stem cells (CSCs), that have the capacity for self-renewal, tumor initiation, and generation of nontumorigenic progeny. Despite their potentially key role in tumor establishment and m...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.188292.112
更新日期:2012-09-01 00:00:00
abstract::The ETS transcription factors perform distinct biological functions despite conserving a highly similar DNA-binding domain. One distinguishing property of a subset of ETS proteins is a conserved region of 80 amino acids termed the Pointed (PNT) domain. Using enzyme kinetics we determined that the Ets-1 PNT domain cont...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.950902
更新日期:2002-01-01 00:00:00
abstract::Interactions required for inhibition of poly(A) polymerase (PAP) by the U1 snRNP-specific U1A protein, a reaction whose function is to autoregulate U1A protein production, are examined. PAP inhibition requires a substrate RNA to which at least two molecules of U1A protein can bind tightly, but we demonstrate that the ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.11.6.761
更新日期:1997-03-15 00:00:00
abstract::The allosteric and torpedo models have been used for 30 yr to explain how transcription terminates on protein-coding genes. The former invokes termination via conformational changes in the transcription complex and the latter proposes that degradation of the downstream product of poly(A) signal (PAS) processing is imp...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.332833.119
更新日期:2020-01-01 00:00:00
abstract::RNA polymerase II (Pol II) transcribes all protein-coding genes and many noncoding RNAs in eukaryotic genomes. Although Pol II is a complex, 12-subunit enzyme, it lacks the ability to initiate transcription and cannot consistently transcribe through long DNA sequences. To execute these essential functions, an array of...
journal_title:Genes & development
pub_type: 杂志文章,评审
doi:10.1101/gad.335679.119
更新日期:2020-04-01 00:00:00
abstract::The mouse Nedd5 gene encodes a 41.5-kD GTPase similar to the Saccharomyces and Drosophila septins essential for cytokinesis. Nedd5 accumulates near the contractile ring from anaphase through telophase, and finally condenses into the midbody. Microinjection of anti-Nedd5 antibody interferes with cytokinesis, giving ris...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.11.12.1535
更新日期:1997-06-15 00:00:00