β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1

Suriben, Rowena; Kaihara, Kelly A.; Paolino, Magdalena; Reichelt, Mike; Kummerfeld, Sarah; Modrušan, Zora; Dugger, Debra L.; Newton, Kim; Sagolla, Meredith; Webster, Joshua D.; Liu, Jinfeng; Hebrok, Matthias; Dixit, Vishva M.

doi:10.1016/j.cell.2015.10.076

Cited by 43 publications

(47 citation statements)

References 48 publications

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“…1A). Etv5 mRNA has been reported in AT2 cells (1,7), but mRNA expression does not always correlate with the abundance of labile proteins such as Etv5 (22). By immunostaining, we detected Etv5 protein in a subset of AT2 cells expressing surfactant protein c (Sftpc) and in cells expressing both Sftpc and the secretoglobin Scgb1a1 (Fig.…”

Section: Resultsmentioning

confidence: 75%

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Zhang¹,

Newton²,

Kummerfeld³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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102

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Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population, Etv5 deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin-RING ubiquitin ligase CRL4 COP1/DET1 that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation.A lveolar type II (AT2) cells are a stem cell population that self renews and differentiates into alveolar type I (AT1) cells during lung homeostasis or in response to injury (1, 2). They also give rise to lung adenocarcinoma induced by oncogenic Kras (1, 3-5). AT2 cells are derived from bipotent progenitor cells at the sacculation stage (1). In the adult lung, mature AT2 cells also secrete surfactant phospholipids to maintain normal alveolar function. Sustained Kras activity stimulates the self-renewal of AT2 cells, which eventually leads to abnormal tissue growth (1). An AT2 gene-expression signature has been reported (6, 7), but it is unclear how the identity of AT2 cells is specified and maintained.Given that Ras/MAPK signaling is essential for the self-renewal of AT2 cells and for the initiation of lung adenocarcinoma, identification of the transcription factors that are activated by Ras in AT2 cells is a step toward defining the transcriptional programs underlying AT2 stemness. The PEA3 subgroup of the ETS family of transcription factors, comprised of ETS transcription variants 1, 4, and 5 (Etv1, Etv4, and Etv5) (8), is known to be engaged by Ras/MAPK signaling. Etv4 and Etv5 are expressed in distal lung epithelium during development and are involved in branching morphogenesis and epithelial cell differentiation (9-11). Alveolar epithelial cells in the adult lung also express Etv5 (7, 12), but a critical role for Etv5 in this setting remains elusive.PEA3 transcription factors are also implicated in tumorigenesis. Overexpression of ETV1 or ETV4 has been linked to prostate cancer (13,14), and stabilization of ETV1 by mutant, active tyrosine kinase receptor KIT is thought to drive an oncogenic program in gastrointestinal stromal tumors (GIST) (15). ETV1, ETV4, and ETV5 are labile proteins because of their regulation by the ubiquitin-proteasome system. In GIST, ETV1 protein is stabilized by activation of the Ras/MAPK pathway through an unkno...

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Section: Resultsmentioning

confidence: 75%

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Zhang¹,

Newton²,

Kummerfeld³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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102

112

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“…PRDM14, a member of PRDM family and zinc finger proteins involving transcriptional regulators decrease [60]. Another gene, RFWD2 (COP1) is a cancer suppressor and effects human β-Cell Insulin Secretion [61]. Loss of COP1 expression may contribute to tumorigenesis and regulate the expression of tumor suppressor TP53 [18, 62, 63].…”

Section: Resultsmentioning

confidence: 99%

Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia

Lee

Huang

2016

BMC Med Genomics

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BackgroundEpigenetics of schizophrenia provides important information on how the environmental factors affect the genetic architecture of the disease. DNA methylation plays a pivotal role in etiology for schizophrenia. Previous studies have focused mostly on the discovery of schizophrenia-associated SNPs or genetic variants. As postmortem brain samples became available, more and more recent studies surveyed transcriptomics of the diseases. In this study, we constructed protein-protein interaction (PPI) network using the disease associated SNP (or genetic variants), differentially expressed disease genes and differentially methylated disease genes (or promoters). By combining the different datasets and topological analyses of the PPI network, we established a more comprehensive understanding of the development and genetics of this devastating mental illness.ResultsWe analyzed the previously published DNA methylation profiles of prefrontal cortex from 335 healthy controls and 191 schizophrenic patients. These datasets revealed 2014 CpGs identified as GWAS risk loci with the differential methylation profile in schizophrenia, and 1689 schizophrenic differential methylated genes (SDMGs) identified with predominant hypomethylation. These SDMGs, combined with the PPIs of these genes, were constructed into the schizophrenic differential methylation network (SDMN). On the SDMN, there are 10 hypermethylated SDMGs, including GNA13, CAPNS1, GABPB2, GIT2, LEFTY1, NDUFA10, MIOS, MPHOSPH6, PRDM14 and RFWD2. The hypermethylation to differential expression network (HyDEN) were constructed to determine how the hypermethylated promoters regulate gene expression. The enrichment analyses of biochemical pathways in HyDEN, including TNF alpha, PDGFR-beta signaling, TGF beta Receptor, VEGFR1 and VEGFR2 signaling, regulation of telomerase, hepatocyte growth factor receptor signaling, ErbB1 downstream signaling and mTOR signaling pathway, suggested that the malfunctioning of these pathways contribute to the symptoms of schizophrenia.ConclusionsThe epigenetic profiles of DNA differential methylation from schizophrenic brain samples were investigated to understand the regulatory roles of SDMGs. The SDMGs interplays with SCZCGs in a coordinated fashion in the disease mechanism of schizophrenia. The protein complexes and pathways involved in SDMN may be responsible for the etiology and potential treatment targets. The SDMG promoters are predominantly hypomethylated. Increasing methylation on these promoters is proposed as a novel therapeutic approach for schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0229-y) contains supplementary material, which is available to authorized users.

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“…One possible mechanism of posttranscriptional control of PEA3 group transcription factor levels in T FH cells is proteasomal degradation mediated by E3 ubiquitin ligase COP1 (also known as RFWD2). COP1-mediated degradation of PEA3 group transcription factors is involved in regulation of prostate cancer progression61, β-cell insulin secretion62 and lung-branching morphogenesis63, but the function of COP1 in T FH cell development has not been determined. Because Rfwd2 is expressed in T lymphocytes64, one interesting follow-up would be to examine whether COP1 regulates T FH cell differentiation through degradation of ETV5 or other PEA3 group transcription factors in T cells.…”

Section: Discussionmentioning

confidence: 99%

Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

Park

Lee

et al. 2017

Nat Commun

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High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (TFH) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of TFH cells and GC responses in a T-cell-intrinsic manner. ETV5 expression is derepressed in Cic null TFH cells and knockdown of Etv5 suppresses the enhanced TFH cell differentiation in Cic-deficient CD4+ T cells, suggesting that Etv5 is a critical CIC target gene in TFH cell differentiation. Furthermore, we identify Maf as a downstream target of the CIC–ETV5 axis in this process. These data demonstrate that CIC maintains T-cell homeostasis and negatively regulates TFH cell development and autoimmunity.

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β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1

Cited by 43 publications

References 48 publications

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia

Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

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