dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats

Baladrón, Victoriano; Ruiz-Hidalgo, Marı́a José; Nueda, María Luisa; Díaz-Guerra, María José; Garcı́a-Ramı́rez, José J.; Bonvini, Ezio; Gubina, Elena; Laborda, Jorge

doi:10.1016/j.yexcr.2004.10.001

Cited by 187 publications

(196 citation statements)

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“…On the other hand, Notch1 can cause growth arrest in medulloblastomas, mammalian skin tumors, and small-cell lung cancers (Sriuranpong et al, 2001;Nicolas et al, 2003;Fan et al, 2004). DLK1 is a negative regulator of Notch1 activation and decreases expression of Hes-1 (a downstream target of Notch-1) in 3T3-L1 fibroblasts (Baladron et al, 2005). In this study, we found that the expression of Hes-1 was decreased in DLK1-overexpressing GBM cells and GBM cells grown in DLK1-enriched cultured medium.…”

Section: Discussionmentioning

confidence: 99%

“…DLK1 downregulates expression of Hes-1 A previous study reported that DLK1 may function as a negative regulator of Notch1 signaling; these investigators found that increased DLK1 expression was associated with decreased Hes-1 expression in either confluent Balb/c 14 cells or 3T3-L1 preadipocytes (Baladron et al, 2005). We examined the effect of DLK1 on expression of Hes-1 in glioma cells by realtime RT-PCR.…”

Section: Dlk1 Promotes Proliferation Of Gbm Cellsmentioning

confidence: 99%

“…DLK1 participates in several differentiation processes including adipogenesis (Smas and Sul, 1993;Boney et al, 1996;Garces et al, 1999), hematopoiesis (Moore et al, 1997;Bauer et al, 1998;Kaneta et al, 2000), and adrenal gland development (Cooper et al, 1990;Gaetano et al, 1992), as well as wound healing (Samulewicz et al, 2002); it is also involved in the control of embryonic growth (Schmidt et al, 2000;Takada et al, 2000;Moon et al, 2002). A recent report suggests that DLK1 acts as a negative regulator of Notch1 (Baladron et al, 2005).…”

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DLK1: increased expression in gliomas and associated with oncogenic activities

et al. 2006

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DLK1 (delta-like) is a transmembrane and secreted protein in the epidermal growth factor-like homeotic family. Although expressed widely during embryonic development, only a few tissues retain the expression in adults. Neuroendocrine tumors often highly express this protein; therefore, we hypothesized that brain tumors might also express it. This study found that the expression of DLK1 in gliomas was higher than that in normal brain (Po0.05). After stable transfection of a DLK1 cDNA expression vector into GBM cell lines, their proliferation was increased. Furthermore, they lost contact inhibition, had enhanced anchorage-independent growth in soft agar, and had significantly greater capacity to migrate. Western blot studies showed that expression of cyclin D1, CDK2, and E2F4 were increased, and Rb levels were decreased in these cells. DLK1 was found on the cell surface and secreted in the medium from the transfected GBM cells. DLK1-enriched condition medium stimulated the growth of glioblastoma multiforme cell lines and explants. DLK1 antibody blocked cell growth stimulated by DLK1. In summary, these results suggest that DLK1 may play a role in the formation or progression of gliomas.

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Section: Discussionmentioning

confidence: 99%

Section: Dlk1 Promotes Proliferation Of Gbm Cellsmentioning

confidence: 99%

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DLK1: increased expression in gliomas and associated with oncogenic activities

et al. 2006

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“…In contrast to other members of Delta/Notch/Serrate family, dlk1 protein does not have the DSL (Delta, Serrate, and LAG2) domain mediating NotchDelta interaction, and thus it is not known whether dlk1 functions as a ligand or as a receptor (6). However, recent data based on a yeast two-hybrid system suggested that dlk1 interacts with Notch 1 and inhibits Notch signaling (20). Also, other signaling pathways have been demonstrated to be affected by the expression of Dlk1, e.g.…”

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confidence: 99%

dlk1/FA1 Regulates the Function of Human Bone Marrow Mesenchymal Stem Cells by Modulating Gene Expression of Pro-inflammatory Cytokines and Immune Response-related Factors

Abdallah

Boissy

Tan

et al. 2007

Journal of Biological Chemistry

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dlk1/FA1 (delta-like 1/fetal antigen-1) is a member of the epidermal growth factor-like homeotic protein family whose expression is known to modulate the differentiation signals of mesenchymal and hematopoietic stem cells in bone marrow. We have demonstrated previously that Dlk1 can maintain the human bone marrow mesenchymal stem cells (hMSC) in an undifferentiated state. To identify the molecular mechanisms underlying these effects, we compared the basal gene expression pattern in Dlk1-overexpressing hMSC cells (hMSC-dlk1) versus control hMSC (negative for Dlk1 expression) by using Affymetrix HG-U133A microarrays. In response to Dlk1 expression, 128 genes were significantly up-regulated (with >2-fold; p < 0.001), and 24% of these genes were annotated as immune response-related factors, including pro-inflammatory cytokines, in addition to factors involved in the complement system, apoptosis, and cell adhesion. Also, addition of purified FA1 to hMSC up-regulated the same factors in a dose-dependent manner. As biological consequences of up-regulating these immune response-related factors, we showed that the inhibitory effects of dlk1 on osteoblast and adipocyte differentiation of hMSC are associated with Dlk1-induced cytokine expression. Furthermore, Dlk1 promoted B cell proliferation, synergized the immune response effects of the bacterial endotoxin lipopolysaccharide on hMSC, and led to marked transactivation of the NF-B. Our data suggest a new role for Dlk1 in regulating the multiple biological functions of hMSC by influencing the composition of their microenvironment "niche." Our findings also demonstrate a role for Dlk1 in mediating the immune response.

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“…DLK1 and DLK2 both contain six EGF-like repeats in the extracellular region, a single transmembrane region and a short intracellular tail. 15,16 Despite lacking the characteristic Delta, Serrate and Lag-2 (DSL) domain of canonical Notch ligands, DLK1 and DLK2 interact with Notch1 and serve as antagonists to DLL4-and Jagged1-mediated activation of Notch signaling [17][18][19] that are required for normal vascular maturation. 20 Consistent with previous reports that the Dlk1 and Dlk2 genes reciprocally regulate each other's expression, 16 we report that targeted therapeutic vaccination against DLK1 in RENCAbearing mice leads to the loss of DLK1 expression in the TME, but also to a compensatory increase in the expression of DLK2 by tumor-associated vascular pericytes.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

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When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8 C T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes. Vaccines targeting both DLK1 and DLK2 resulted in superior antitumor benefits in association with improved activation and recruitment of antigen-specific Type 1 CD8 C T cells, reduced presence of myeloid-derived suppressive cells, T regulatory cell and tumor vascular normalization. The antitumor efficacy of vaccines coordinately targeting DLK1 and DLK2 was further improved by inclusion of PD-L1 blockade, thus defining a combination immunotherapy theoretically suitable for the treatment of a broad range of solid (vascularized) cancers.

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dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats

Cited by 187 publications

References 109 publications

DLK1: increased expression in gliomas and associated with oncogenic activities

DLK1: increased expression in gliomas and associated with oncogenic activities

dlk1/FA1 Regulates the Function of Human Bone Marrow Mesenchymal Stem Cells by Modulating Gene Expression of Pro-inflammatory Cytokines and Immune Response-related Factors

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

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