Abstract:
:Neurofibromas are common tumors found in neurofibromatosis type 1 (NF1) patients. These complex tumors are composed of Schwann cells, mast cells, fibroblasts and perineurial cells embedded in collagen that provide a lattice for tumor invasion. Genetic studies demonstrate that in neurofibromas, nullizygous loss of Nf1 in Schwann cells and haploinsufficiency of Nf1 in non-neuronal cells are required for tumorigenesis. Fibroblasts are a major cellular constituent in neurofibromas and are a source of collagen that constitutes approximately 50% of the dry weight of the tumor. Here, we show that two of the prevalent heterozygous cells found in neurofibromas, mast cells and fibroblasts interact directly to contribute to tumor phenotype. Nf1+/- mast cells secrete elevated concentrations of the profibrotic transforming growth factor-beta (TGF-beta). In response to TGF-beta, both murine Nf1+/- fibroblasts and fibroblasts from human neurofibromas proliferate and synthesize excessive collagen, a hallmark of neurofibromas. We also establish that the TGF-beta response occurs via hyperactivation of a novel Ras-c-abl signaling pathway. Genetic or pharmacological inhibition of c-abl reverses fibroblast proliferation and collagen synthesis to wild-type levels. These studies identify a novel molecular target to inhibit neurofibroma formation.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Yang FC,Chen S,Clegg T,Li X,Morgan T,Estwick SA,Yuan J,Khalaf W,Burgin S,Travers J,Parada LF,Ingram DA,Clapp DWdoi
10.1093/hmg/ddl165subject
Has Abstractpub_date
2006-08-15 00:00:00pages
2421-37issue
16eissn
0964-6906issn
1460-2083pii
ddl165journal_volume
15pub_type
杂志文章abstract::Splicing regulation is an important step of post-transcriptional gene regulation. It is a highly dynamic process orchestrated by RNA-binding proteins (RBPs). RBP dysfunction and global splicing dysregulation have been implicated in many human diseases, but the in vivo functions of most RBPs and the splicing outcome up...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2016-12-01 00:00:00
abstract::Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger...
journal_title:Human molecular genetics
pub_type: 杂志文章
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abstract::Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. SMA is caused by loss of functional survival motor neuron 1 (SMN1), resulting in death of spinal motor neurons. Current therapeutic research focuses on modulating the expression of a partially functioning copy gene, SMN2, which is reta...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn426
更新日期:2009-03-15 00:00:00
abstract::The huntingtin interacting protein (HIP1) is enriched in membrane-containing cell fractions and has been implicated in vesicle trafficking. It is a multidomain protein containing an N-terminal ENTH domain, a central coiled-coil forming region and a C-terminal actin-binding domain. In the present study we have identifi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.17.1807
更新日期:2001-08-15 00:00:00
abstract::Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified gen...
journal_title:Human molecular genetics
pub_type: 杂志文章
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abstract::Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine expansion in the disease protein, huntingtin. In HD patients and transgenic mice, the affected neurons form characteristic ubiquitin-positive nuclear inclusions (NIs). We have established ecdysone-inducible stable mou...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2000-08-12 00:00:00
abstract::Primary open-angle glaucoma (POAG) is a genetically complex neuropathy that affects retinal ganglion cells and is a leading cause of blindness worldwide. WDR36, a gene of unknown function, was recently identified as causative for POAG at locus GLC1G. Subsequent studies found disease-associated variants in control popu...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2008-08-15 00:00:00
abstract::Friedreich's ataxia is a neurodegenerative disorder caused by mutations in the frataxin gene that produces a predominantly mitochondrial protein whose primary function appears to be mitochondrial iron-sulfur cluster (ISC) biosynthesis. Previously we demonstrated that frataxin interacts with multiple components of the ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr582
更新日期:2012-04-01 00:00:00
abstract::ARHI has been identified as a maternally imprinted tumor suppressor gene that maps to chromosome 1p31 and whose expression is markedly down-regulated in breast cancer. To explore possible mechanisms that could silence ARHI expression, we have tested the importance of DNA methylation, histone acetylation and histone me...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg204
更新日期:2003-08-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章,评审
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更新日期:2005-04-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq565
更新日期:2011-03-15 00:00:00
abstract::We previously identified Peg1/Mest as a novel paternally expressed gene in the developing mouse embryo. The human PEG1 gene was recently assigned to 7q32 and shown to be imprinted and paternally expressed. Therefore, PEG1 deficiency could participate in the aetiology of pre- and post-natal growth retardation associate...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.11.1907
更新日期:1997-10-01 00:00:00
abstract::We have constructed a long-range restriction map of the region on chromosome 4q that contains the gene for facioscapulohumeral muscular dystrophy (FSHD). This region contains the linkage group cen ... D4S163-D4S139-D4F35S1-D4F104S1-FSHD ... 4qter, which spans a genetic distance of about 5 cM. Pulse field gel electroph...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.10.1667
更新日期:1993-10-01 00:00:00
abstract::Bitter taste perception is initiated by TAS2R receptors, which respond to agonists by triggering depolarization of taste bud cells. Mutations in TAS2Rs are known to affect taste phenotypes by altering receptor function. Evidence that TAS2Rs overlap in ligand specificity suggests that they may also contribute joint eff...
journal_title:Human molecular genetics
pub_type: 临床试验,杂志文章
doi:10.1093/hmg/ddr252
更新日期:2011-09-01 00:00:00
abstract::We have constructed a YAC contig containing 54 clones and a minimum of 7 Mbp of human DNA, that maps to bands q34-35 on chromosome 5. The contig was nucleated using FISH mapped cosmid clones shown to flank the t(2;5)(p23;q35) translocation breakpoint in a CD30-positive large cell lymphoma cell line. Thirty of the 54 Y...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.1.99
更新日期:1994-01-01 00:00:00
abstract::Little is known about the post-transcriptional mechanisms that modulate the genetic effects in the molecular pathways underlying Alzheimer disease (AD), and even less is known about how these changes might differ across diverse populations. RNA editing, the process that alters individual bases of RNA, may contribute t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz110
更新日期:2019-09-15 00:00:00
abstract::Apoptosis is a morphologically distinct form of cell death involved in many physiological and pathological processes. The regulation of Fas/Apo-1 involved in membrane-mediated apoptosis has also been known to play crucial roles in many systems. More and more naturally occurring antisense RNAs are now known to regulate...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi156
更新日期:2005-06-01 00:00:00
abstract::Intracellular accumulations of mutant, misfolded proteins are major pathological hallmarks of amyotrophic lateral sclerosis (ALS) and related disorders. Recently, mutations in Sigma receptor 1 (SigR1) have been found to cause a form of ALS and frontotemporal lobar degeneration (FTLD). Our goal was to pinpoint alterati...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt008
更新日期:2013-04-15 00:00:00
abstract::The term 'dynamic mutation' was introduced to distinguish the unique properties of expanding, unstable DNA repeat sequences from other forms of mutation. The past decade has seen dynamic mutations uncovered as the molecular basis for a growing number of human genetic diseases and for all of the characterized 'rare' ch...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/10.20.2187
更新日期:2001-10-01 00:00:00
abstract::Williams syndrome (WS) is a neurodevelopmental disorder caused by a 1.5-1.8 Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of WS include cardiovascular problems, craniofacial dysmorphology, deficits in visual-spatial cognition and a characteristic hypersocial personality. Ther...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2019-10-15 00:00:00
abstract::A long-term goal of modeling Huntington's disease (HD) is to recapitulate the cardinal features of the disease in mice that express both mutant and wild-type (WT) huntingtin (Htt), as HD commonly manifests as a heterozygous condition in humans, and loss of WT Htt is associated with loss-of-function. In a new heterozyg...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu166
更新日期:2014-09-01 00:00:00
abstract::A long-standing question concerning X-chromosome inactivation (XCI) has been how some genes avoid the otherwise stable chromosome-wide heterochromatinization of the inactive X chromosome. As 20% or more of human X-linked genes escape from inactivation, such genes are an important contributor to sex differences in gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2018-04-01 00:00:00
abstract::The congenital malformation split hand/foot (SHFM) is characterized by missing central fingers and dysmorphology or fusion of the remaining ones. Type-1 SHFM is linked to deletions/rearrangements of the DLX5-DLX6 locus and point mutations in the DLX5 gene. The ectrodactyly phenotype is reproduced in mice by the double...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2016-02-15 00:00:00
abstract::The molecular genetic events underlying endometrial tumorigenesis are ill-defined at present. We have identified a region on the short arm of chromosome 1 which is frequently deleted in endometrial cancers. The region of deletion has been localized to bands 1p32-33. Deletion of 1p32-33 is seen more frequently in cance...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.7.1017
更新日期:1996-07-01 00:00:00
abstract::Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulate...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu068
更新日期:2014-07-01 00:00:00
abstract::Neurodevelopmental disorders frequently share common clinical features and appear high rate of comorbidity, such as those present in patients with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). While characterizing behavioral phenotypes in the mouse model of cyclin-dependent kinas...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2017-10-15 00:00:00
abstract::Autosomal dominant familial spastic paraplegia (FSP) is a genetically heterogeneous neurodegenerative disorder displaying anticipation for which three loci have been mapped to the chromosomal positions 14q11.2-q24.3 (SPG3), 2p21-p24 (SPG4) and 15q11.1 (SPG6). The repeat expansion detection (RED) method has been used t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.11.1779
更新日期:1998-10-01 00:00:00
abstract::Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation syndrome that maps to human chromosome 11p15.5, a region that harbours a number of imprinted genes. We studied the methylation status of H19 and KCNQ1OT1 (LIT1/KvDMR1) in a large series of BWS patients. Different patient groups were identified: group I pa...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2001-03-01 00:00:00
abstract::Several known or putative glycosyltransferases are required for the synthesis of laminin-binding glycans on alpha-dystroglycan (αDG), including POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP, ISPD and GTDC2. Mutations in these glycosyltransferase genes result in defective αDG glycosylation and reduced ligand binding by α...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt021
更新日期:2013-05-01 00:00:00
abstract::With progress in genome-wide association studies of depression, from identifying zero hits in ~16 000 individuals in 2013 to 223 hits in more than a million individuals in 2020, understanding the genetic architecture of this debilitating condition no longer appears to be an impossible task. The pressing question now i...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa115
更新日期:2020-09-30 00:00:00