Abstract:
:Organization into polarized three-dimensional structures defines whether epithelial cells are normal or malignant. In a model of morphogenesis, we show that inhibiting key signaling pathways in human breast cancer cells leads to "phenotypic reversion" of the malignant cells. Using architecture as an endpoint, we report that, in all cases, signaling through Raf/MEK/ERK disrupted tissue polarity via matrix metalloproteinase9 (MMP9) activity. Induction of Raf or activation of an engineered, functionally inducible MMP9 in nonmalignant cells led to loss of tissue polarity, and reinitiated proliferation. Conversely, inhibition of Raf or MMP9 with small molecule inhibitors or shRNAs restored the ability of cancer cells to form polarized quiescent structures. Silencing MMP9 expression also reduced tumor growth dramatically in a murine xenograft model. LC-MS/MS analysis comparing conditioned medium from nonmalignant cells with or without active MMP9 revealed laminin 111 (LM1) as an important target of MMP9. LM1 has been implicated in acinar morphogenesis; thus, its degradation by MMP9 provides a mechanism for loss of tissue polarity and reinitiation of growth associated with MMP9 activity. These findings underscore the importance of the dynamic reciprocity between the extracellular matrix integrity, tissue polarity, and Raf/MEK/ERK and MMP9 activities, providing an axis for either tissue homeostasis or malignant progression.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Beliveau A,Mott JD,Lo A,Chen EI,Koller AA,Yaswen P,Muschler J,Bissell MJdoi
10.1101/gad.1990410subject
Has Abstractpub_date
2010-12-15 00:00:00pages
2800-11issue
24eissn
0890-9369issn
1549-5477pii
24/24/2800journal_volume
24pub_type
杂志文章abstract::The c-fos serum response element (SRE) is a multifunctional regulatory region of the c-fos promoter that responds to a variety of inducers. Recently, we have demonstrated that the SRE binds the C/EBP-related transcription factor rat NFIL-6 (rNFIL-6). In this study we show that rNFIL-6 is regulated by the cAMP second m...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.5.10.1754
更新日期:1991-10-01 00:00:00
abstract::The gamma delta T-cell receptor (TCR) is the first TCR to be expressed in ontogeny in all vertebrates in which it has been examined thoroughly. Murine gamma delta cell-surface protein is detected by the fourteenth day of gestation. In this work, the activation of gamma delta RNA has been studied. Data indicate that th...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.4.8.1304
更新日期:1990-08-01 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::Mutations in the CSA or CSB complementation genes cause the Cockayne syndrome, a severe genetic disorder that results in patients' death in early adulthood. CSA and CSB act in a transcription-coupled repair (TCR) pathway, but their functional relationship is not understood. We have previously shown that CSA is a subun...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.378206
更新日期:2006-06-01 00:00:00
abstract::The alternatively spliced exon EIIIB is regulated in a cell type-specific manner in the rat fibronectin gene. Splicing of EIIIB into fibronectin mRNA is dependent on sequences in the intron immediately downstream of EIIIB. We show that a short, highly repeated TGCATG motif in this intron is important for cell type-spe...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.8.13.1561
更新日期:1994-07-01 00:00:00
abstract::A powerful enhancer has been mapped to an 18-bp DNA segment located 11 kb 5' to the human epsilon-globin gene within the dominant control or locus-activating region. This enhancer is inducible in K562 human erythroleukemia cells, increasing linked gamma-globin promoter/luciferase gene expression to 170-fold over an en...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.4.6.993
更新日期:1990-06-01 00:00:00
abstract::The mechanisms that control energy homeostasis and tissue growth during development are closely linked through the insulin signal transduction pathway. Changes in the level of insulin and other hormones reflect the nutritional status of the animal to control circulating sugar levels and fat metabolism. Systemic defect...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.374406
更新日期:2006-02-15 00:00:00
abstract::A euchromatic gene placed in the vicinity of heterochromatin by a chromosomal rearrangement generally exhibits position effect variegation (PEV), a clonally inherited pattern showing gene expression in some somatic cells but not in others. The mechanism responsible for this loss of gene expression is investigated here...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.10.1263
更新日期:1995-05-15 00:00:00
abstract::The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 ar...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.305037.117
更新日期:2017-10-15 00:00:00
abstract::Mammalian telomeres are coated by the sequence-specific, DNA-binding protein, TRF1, a negative regulator of telomere length. Previous results showed that ADP-ribosylation of TRF1 by tankyrase 1 released TRF1 from telomeres and promoted telomere elongation. We now show that loss of TRF1 from telomeres results in ubiqui...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1077103
更新日期:2003-06-01 00:00:00
abstract::The ATR (ATM and Rad3-related) kinase and its regulatory partner ATRIP (ATR-interacting protein) coordinate checkpoint responses to DNA damage and replication stress. TopBP1 functions as a general activator of ATR. However, the mechanism by which TopBP1 activates ATR is unknown. Here, we show that ATRIP contains a Top...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1666208
更新日期:2008-06-01 00:00:00
abstract::Cell cycle checkpoints are critical for genomic stability. Rad17, a component of the checkpoint clamp loader complex (Rad17/Rfc2-5), is required for the response to DNA damage and replication stress. To explore the role of Rad17 in the maintenance of genomic integrity, we established somatic conditional alleles of RAD...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1065103
更新日期:2003-04-15 00:00:00
abstract::The bcl-6 proto-oncogene encodes a POZ/zinc finger transcriptional repressor expressed in germinal center (GC) B and T cells and required for GC formation and antibody affinity maturation. Deregulation of bcl-6 expression by chromosomal rearrangements and point mutations of the bcl-6 promoter region are implicated in ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.13.1953
更新日期:1998-07-01 00:00:00
abstract::Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be in...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.275453.115
更新日期:2016-02-15 00:00:00
abstract::Histone methylation plays an important role in regulating gene expression. One such methylation occurs at Lys 79 of histone H3 (H3K79) and is catalyzed by the yeast DOT1 (disruptor of telomeric silencing) and its mammalian homolog, DOT1L. Previous studies have demonstrated that germline disruption of Dot1L in mice res...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.2018511
更新日期:2011-02-01 00:00:00
abstract::Previous genetic mosaic studies established that expression of the Drosophila bride of sevenless (boss) gene is required in photoreceptor neuron R8 for the development of photoreceptor neuron R7. This led to the proposal that boss encodes or regulates an R7-specific inductive cue. We have identified the boss gene base...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.4.11.1835
更新日期:1990-11-01 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::Telomere proteins protect the chromosomal terminus from nucleolytic degradation and end-to-end fusion, and they may contribute to telomere length control and the regulation of telomerase. The current studies investigate the effect of Oxytricha single-stranded telomere DNA-binding protein subunits alpha and beta on tel...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.10.1504
更新日期:1998-05-15 00:00:00
abstract::The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of steroid hormones and xenochemicals including prescription drugs. Nuclear receptor SXR/PXR (steroid and xenobiotic receptor/pregnenolone X receptor) has been shown both biochemically and genetically to activate CYP3A gen...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.846800
更新日期:2000-12-01 00:00:00
abstract::DNA repair associated with DNA replication is important for the conservation of genomic sequence information, whereas reconstitution of chromatin after replication sustains epigenetic information. We have isolated and characterized mutations in the BRU1 gene of Arabidopsis that suggest a novel link between these under...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.295404
更新日期:2004-04-01 00:00:00
abstract::Using an immunochemical approach, we have identified a unique antigen, PEP (protein on ecdysone puffs), which is associated in third-instar larvae with the active ecdysone-regulated loci on polytene chromosomes; PEP is not associated with most intermolt puffs and is found on some, but not all, heat shock-induced puffs...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.5.2.188
更新日期:1991-02-01 00:00:00
abstract::The SNF1 protein kinase is broadly conserved in eukaryotes and has been implicated in responses to environmental and nutritional stress. In yeast, the SNF1 kinase has a central role in the response to glucose starvation. SNF1 is associated with its activating subunit, SNF4, and other proteins in complexes. Using the t...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.24.3105
更新日期:1996-12-15 00:00:00
abstract::Two retrovirus promoter trap vectors (U3His and U3Neo) have been used to disrupt genes expressed in totipotent murine embryonal stem (ES) cells. Selection in L-histidinol or G418 produced clones in which the coding sequences for histidinol-dehydrogenase or neomycin-phosphotransferase were fused to sequences in or near...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.6.6.919
更新日期:1992-06-01 00:00:00
abstract::cappuccino and spire are unique Drosophila maternal-effect loci that participate in pattern formation in both the anteroposterior and dorsoventral axes of the early embryo. Mutant females produce embryos lacking pole cells, polar granules, and normal abdominal segmentation. They share these defects with the posterior ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.3.9.1437
更新日期:1989-09-01 00:00:00
abstract::The number of known long noncoding RNA (lncRNA) functions is rapidly growing, but how those functions are encoded in their sequence and structure remains poorly understood. NORAD (noncoding RNA activated by DNA damage) is a recently characterized, abundant, and highly conserved lncRNA that is required for proper mitot...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.309138.117
更新日期:2018-01-01 00:00:00
abstract::Human ELAV proteins are implicated in cell growth and differentiation via regulation of mRNA expression in the cytoplasm. In human embryonic teratocarcinoma (hNT2) cells transfected with the human neuronal ELAV-like protein, Hel-N1, neurites formed, yet cells were not terminally differentiated. Cells in which neurite ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.13.4.449
更新日期:1999-02-15 00:00:00
abstract::One of the central requirements for eukaryotic chromosome stability is the maintenance of the simple sequence tracts at telomeres. In this study, we use genetic and physical assays to reveal the nature of a novel mechanism by which telomere length is controlled. This mechanism, telomeric rapid deletion (TRD), is capab...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.11.1310
更新日期:1996-06-01 00:00:00
abstract::We report the discovery of mRNA 5'-leader trans-splicing (SL trans-splicing) in the chordates. In the ascidian protochordate Ciona intestinalis, the mRNAs of at least seven genes undergo trans-splicing of a 16-nucleotide 5'-leader apparently derived from a 46-nucleotide RNA that shares features with previously charact...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.865401
更新日期:2001-02-01 00:00:00
abstract::We characterized a gene, extradenticle, which seems to interact with a specific subset of Drosophila homeo domain proteins, possibly affecting their target specificity. This interpretation is based on an examination of the zygotic and maternal effect phenotypes of extradenticle mutations. In embryos with reduced level...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.4.7.1209
更新日期:1990-07-01 00:00:00
abstract::Structural cell-surface and extracellular-matrix proteins modulate intercellular signaling events during development, but how this is achieved remains largely unknown. Here we identify a novel family of Drosophila proteins, Nasrat and Polehole, that coat the oocyte surface and play two roles: They mediate assembly of ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.223902
更新日期:2002-04-15 00:00:00