Abstract:
:Lineage-restricted transcription factors (TFs) are frequently mutated or overexpressed in cancer and contribute toward malignant behaviors; however, the molecular bases of their oncogenic properties are largely unknown. As TF activities are difficult to inhibit directly with small molecules, the genes and pathways they regulate might represent more tractable targets for drug therapy. We studied GATA6, a TF gene that is frequently amplified or overexpressed in gastric, esophageal and pancreatic adenocarcinomas. GATA6-overexpressing gastric cancer cell lines cluster in gene expression space, separate from non-overexpressing lines. This expression clustering signifies a shared pathogenic group of genes that GATA6 may regulate through direct cis-element binding. We used chromatin immunoprecipitation and sequencing (ChIP-seq) to identify GATA6-bound genes and considered TF occupancy in relation to genes that respond to GATA6 depletion in cell lines and track with GATA6 mRNA (synexpression groups) in primary gastric cancers. Among other cellular functions, GATA6-occupied genes control apoptosis and govern the M-phase of the cell cycle. Depletion of GATA6 reduced the levels of the latter transcripts and arrested cells in G2 and M phases of the cell cycle. Synexpression in human tumor samples identified likely direct transcriptional targets substantially better than consideration only of transcripts that respond to GATA6 loss in cultured cells. Candidate target genes responded to the loss of GATA6 or its homolog GATA4 and even more to the depletion of both proteins. Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. Thus, many downstream effects occur indirectly through other TFs and GATA6 activity in gastric cancer is partially redundant with GATA4. This integrative analysis of locus occupancy, gene dependency and synexpression provides a functional signature of GATA6-overexpressing gastric cancers, revealing both limits and new therapeutic directions for a challenging and frequently fatal disease.
journal_name
Oncogenejournal_title
Oncogeneauthors
Sulahian R,Casey F,Shen J,Qian ZR,Shin H,Ogino S,Weir BA,Vazquez F,Liu XS,Hahn WC,Bass AJ,Chan V,Shivdasani RAdoi
10.1038/onc.2013.517subject
Has Abstractpub_date
2014-12-04 00:00:00pages
5637-48issue
49eissn
0950-9232issn
1476-5594pii
onc2013517journal_volume
33pub_type
杂志文章相关文献
ONCOGENE文献大全abstract::In the search for retinoids active against Burkitt's lymphoma (BL), we found that the arotinoid mofarotene (Ro 40-8757) induced strong antiproliferative and apoptotic responses in most established BL cell lines as well as in primary BL cells. Ro 40-8757-induced apoptosis is associated with mitochondrial membrane depol...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206060
更新日期:2003-02-13 00:00:00
abstract::pp60c-src, a cellular tyrosine kinase homologous to the retroviral v-src oncogene, becomes transiently activated during mitosis. Activation is accompanied by phosphorylation of three sites in the amino-terminal regulatory domain of the protein, threonine 34, threonine 46 and serine 72. These sites can be phosphorylate...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1993-03-01 00:00:00
abstract::Granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-5 (IL-5 belong to a family of cytokines that regulate proliferation, differentiation and function of haematopoietic cells. Their receptor consists of a ligand specific alpha-chain and a signal transducing beta-chain (betac)...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202896
更新日期:1999-09-09 00:00:00
abstract::Bid, a pro-apoptotic member of the Bcl-2 family, was initially discovered through binding to both pro-apoptotic Bax and anti-apoptotic Bcl-2. During apoptosis, Bid can be cleaved not only by caspase-8 during death receptor apoptotic signaling, but also by other caspases, granzyme B, calpains and cathepsins. Protease-c...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2009.47
更新日期:2008-12-01 00:00:00
abstract::A recent large multi-centre study convincingly confirmed previous observations that the SYT-SSX1 fusion type, compared to SYT-SSX2, of synovial sarcoma is associated with a worse clinical outcome. Apart from the clinical impact, this fact also suggests (1) that the SYT-SSX fusion gene may influence molecular mechanism...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1205700
更新日期:2002-08-22 00:00:00
abstract::Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional chemotherapy treatment approaches. CLL as a disease entity is defined by a relatively parsimonious set of diagnostic criteria and therefore likely constitutes an umbrella term for multiple relate...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2012.411
更新日期:2013-06-06 00:00:00
abstract::Scribble complex proteins maintain apicobasal polarity, regulate cell fate determination and function as tumour suppressors in epithelial tissue. Despite evidence that the function of Scribble is maintained in the lymphocyte lineage, we still understand little about its role as a tumour suppressor in haematological ma...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2015.167
更新日期:2016-03-03 00:00:00
abstract::Chemoprevention has been widely explored as a promising strategy for controlling the incidence of lung cancer, the leading cause of cancer-related death. To maximize the benefit of lung cancer chemoprevention, it is important to identify individuals at high risk for the disease. The genetic background has been shown t...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206852
更新日期:2003-10-16 00:00:00
abstract::SIAH-1 and SIAH-2 are the human members of an evolutionary highly conserved E3 ligase family. SIAH-1 is a p53 and p21(Waf-1/Cip-1) induced gene during apoptosis and tumor suppression. In stable-transfected clones of MCF-7 cells, SIAH-1 overexpression was associated with apoptosis, mitotic alterations and p21(Waf-1/Cip...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206994
更新日期:2003-12-04 00:00:00
abstract::P53 is a tumor suppressor gene that plays a crucial role in suppressing tumorigenesis by inducing either cell cycle arrest or apoptosis in cells with DNA damage. In more than 50% of tumors p53 is inactivated by gene mutations. However, there have also been reports of tumor cells in which p53 remains wild type and is p...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210110
更新日期:2007-05-10 00:00:00
abstract::In order to obtain insight into the parameters determining the subcellular localization of mutant and wild-type forms of p53, we analysed the subcellular distribution of p53 in four Balb/c mouse-derived cell lines ranging in their cellular phenotypes from normal (3T3), via minimal transformant (T3T3), to maximally tra...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1992-07-01 00:00:00
abstract::The FoxO family of Forkhead transcription factors plays an important role in longevity and tumor suppression by upregulating target genes involved in stress resistance, metabolism, cell cycle arrest and apoptosis. FoxO transcription factors translate a variety of environmental stimuli, including insulin, growth factor...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2008.21
更新日期:2008-04-07 00:00:00
abstract::Ultraviolet light (UV) induced DNA lesions efficiently block transcript elongation and induce the p53 response. Although p53 contributes to transcriptional activation of the p21waf1 and bax genes, accumulation of these proteins requires that these genes are free of UV induced pyrimidine dimers. We assessed the level o...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201963
更新日期:1998-08-06 00:00:00
abstract::Resistance of pancreatic cancer to current treatments including radiotherapy remains a major challenge in oncology and may be caused by defects in apoptosis programs. Since 'inhibitor of apoptosis proteins' (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210502
更新日期:2007-10-25 00:00:00
abstract::The E6 proteins of specific cancer-associated human papillomaviruses (HPVs) complex with and mediate degradation of the cellular anti-oncogene p53 in vitro. A critical property of p53 is its ability to stimulate transcription from promoters containing its recognition sequence. HPV E6, mutant p53 proteins, and several ...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1995-02-02 00:00:00
abstract::Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2015.281
更新日期:2016-04-28 00:00:00
abstract::Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine / threonine kinase and participates in a signaling complex that regulates both proliferation and apoptosis to ensure the proper size and shape of the fly. Human counterparts of this complex have been found to be frequently downregulated or mu...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208682
更新日期:2005-08-11 00:00:00
abstract::The signal transduction pathways, orchestrating the differentiation of hematopoietic stem and progenitor cells in response to cytokine stimulation, are strictly controlled by networks of feedback loops, highly selective protein interactions and finely tuned on/off switches. In hematological malignancies, the aberrant ...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2012.435
更新日期:2013-06-27 00:00:00
abstract::Melanoma is the most aggressive form of skin cancer and is notoriously resistant to all current modalities of cancer therapy. A large set of genetic, functional and biochemical studies suggest that melanoma cells become 'bullet proof' against a variety of chemotherapeutic drugs by exploiting their intrinsic resistance...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1206454
更新日期:2003-05-19 00:00:00
abstract::Bone morphogenetic protein 3B (BMP3B) is a member of the TGF-beta superfamily. The BMP3B promoter sequence was previously identified as a target for aberrant DNA methylation in non-small-cell lung cancer (NSCLC). Aberrant DNA hypermethylation in the BMP3B promoter is associated with downregulation of BMP3B transcripti...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1207441
更新日期:2004-04-29 00:00:00
abstract::Chromosomal aberrations are a hallmark of human cancers, with complex cytogenetic rearrangements leading to genetic changes permissive for cancer initiation and progression. Protection of Telomere 1 (POT1) is an essential component of the shelterin complex and functions to maintain chromosome stability by repressing t...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2016.405
更新日期:2017-04-06 00:00:00
abstract::Leukocyte tyrosine kinase (LTK) is a receptor tyrosine kinase which belongs to the insulin receptor superfamily and is mainly expressed in pre-B lymphocytes and neuronal tissues. Recently, we demonstrated that LTK utilizes Shc and IRS-1 as two major substrates and while both equally activate the Ras pathway, only IRS-...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201153
更新日期:1997-06-26 00:00:00
abstract::Dysregulated microRNA (miRNA) mediate malignant phenotypes, including metabolic reprogramming. By performing an integrative analysis of miRNA and metabolome data for the NCI-60 cell line panel, we identified an miRNA cluster strongly associated with both c-Myc expression and global metabolic variation. Within this clu...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2015.333
更新日期:2016-05-01 00:00:00
abstract::The balance of activities between the proto-oncogene phosphoinositide 3-kinase (PI3K) and the tumour suppressor gene PTEN has been shown to affect cellular growth and proliferation, as well as tumorigenesis. Previously, PTEN expression in the PTEN-null Jurkat T cell leukaemia line was shown to cause reduced proliferat...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206872
更新日期:2003-11-06 00:00:00
abstract::The HER-2/neu proto-oncogene is homologous with, but distinct from, the epidermal growth factor receptor. Current evidence indicates that this gene is frequently amplified and/or overexpressed in some human breast and ovarian cancers and that these alterations may be clinically important; however, little is known abou...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1990-07-01 00:00:00
abstract::Genetic suppression of the neoplastic phenotype has been demonstrated in somatic cell hybrids between tumor and normal cells. Suppression in whole-cell and microcell hybrids cannot, as yet, be attributed to specific elements defined at the molecular level. To identify a gene capable of suppressing the neoplastic pheno...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1991-12-01 00:00:00
abstract::Prostate cancer is one of the major causes of cancer-related death in the western world. Androgen-deprivation therapy (ADT) for the suppression of androgens binding to the androgen receptor (AR) has been the norm of prostate cancer treatment. Despite early success to suppress prostate tumor growth, ADT eventually fail...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2010.121
更新日期:2010-06-24 00:00:00
abstract::Two hepatocarcinoma cell lines, the Hepa-1 wild-type (c1c7) and the beta-subunit mutated (c4) lacking hypoxia-inducible factor-1 (HIF-1) activity, were differentially susceptible to apoptosis by hepatocyte growth factor (HGF). The c4 cells were 40% apoptotic 48 h after HGF treatment. On the contrary, the wild-type c1c...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206519
更新日期:2003-06-26 00:00:00
abstract::Although p73alpha induces many of the same cellular events as p53, it is structurally distinct from p53 in that it possesses a unique COOH-terminal domain. To dissect the function of this domain, we performed yeast two-hybrid screening of a HeLa cDNA library using residues 552-636 of p73alpha as bait. Among the clones...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2008.452
更新日期:2009-02-19 00:00:00
abstract::Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures. Here, we show that distinct, stage-wise metabolic alterations in BLCA are associated with the loss of function of aldehyde oxidase (AOX1). AOX1 associated metabolites have a high predictive value for advanced BLCA an...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-019-0902-7
更新日期:2020-10-01 00:00:00