dlk Modulates Mitogen-Activated Protein Kinase Signaling to Allow or Prevent Differentiation

Ruiz-Hidalgo, Marı́a José; Gubina, Elena; Tull, Lori; Baladrón, Victoriano; Laborda, Jorge

doi:10.1006/excr.2001.5464

Cited by 48 publications

(53 citation statements)

References 53 publications

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“…We also investigated if Dlk1 regulates GH expression via a MAP kinase-dependent mechanism. It has been shown that Dlk1 can modulate the activity of the MAP kinase pathway in the presence of growth factors such as insulin and IGF-I [29]. In 3T3 cells, when Dlk-1 expression was knocked down by antisense technology, IGF-I/insulin treatment resulted in a faster and higher-level activation of ERK/MAPK comparing to that in cells with normal Dlk-1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…It has previously been shown that in cells with Dlk-1 expression knocked-down by antisense technology, IGF-I/insulin treatment resulted in a faster and higher-level activation of ERK/ MAPK compared to cells with normal Dlk-1 expression [29]. Furthermore, inhibition of MAP kinase activity has been shown to repress GH promoter activity [30].…”

Section: Dlk1-mediated Gh Regulation Is Independent Of Map Kinasementioning

confidence: 99%

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Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Ansell

Zhou

Schjeide

et al. 2007

Molecular and Cellular Endocrinology

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Delta-like protein 1 (Dlk1) is a transmembrane protein characterized by epidermal growth factor (EGF)-like repeats. Dlk1, which is also known as preadipocyte factor 1 (pref-1) because of its ability to inhibit preadipocyte differentiation, regulates the differentiation of several other cell types through unknown mechanisms. To elucidate Dlk1 functions, identification of Dlk1-regulated target genes is critical. The observation that Dlk1 is expressed in many endocrine tissues suggests that Dlk1 may have endocrine-related functions. Because Dlk1 is expressed in GH producing cells, we hypothesize that one function of Dlk1 is to regulate GH expression. We found that GH mRNA, protein, and secretion were significantly decreased in GH3 pituitary cell clones that stably express Dlk1. In contrast, Dlk1 expression was unable to alter prolactin expression. Co-transfection of GH3 cells with a GH promoter-regulated reporter gene showed that Dlk1 repressed GH promoter activity. Deletion and mutation analysis of the GH promoter indicated that Pit-1 binding sites in the GH promoter are required for Dlk1-mediated repression. Furthermore, Dlk1 expression represses Pit-1-mediated transcription when both proteins are co-expressed in MCF-7 cells. Deletion analysis of Dlk1 revealed that the ability of Dlk1 to regulate GH promoter activity is independent of both its EGF-like repeats and its ability to modulate MAP kinase activity. The observation that Dlk1 regulates GH expression identifies the first endocrine function of Dlk1, establishes GH as a Dlk1-regulated target gene, and provides a model system to facilitate studies of Dlk1-mediated signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Dlk1-mediated Gh Regulation Is Independent Of Map Kinasementioning

confidence: 99%

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Ansell

Zhou

Schjeide

et al. 2007

Molecular and Cellular Endocrinology

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“…Thus, it is conceivable that a Pref-1/FA1-dependent reduction in the density of functional IGF-1Rs on the surface of preadipocytes would result in impaired IGF-1/IGF-1R signaling. In Balb/c 3T3 cells expressing either sense or antisense pref-1/dlk1, no effect of Pref-1/FA1 on IGF-1R levels was observed (58). The reason for this discrepancy remains to be established, but it may be cell line-dependent.…”

Section: Pref-1/fa1-dependent Inhibition Of Adipocyte Differentiationmentioning

confidence: 96%

Insulin-like Growth Factor-1/Insulin Bypasses Pref-1/FA1-mediated Inhibition of Adipocyte Differentiation

Zhang

Nøhr

Jensen

et al. 2003

Journal of Biological Chemistry

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Pref-1 is a highly glycosylated Delta-like transmembrane protein containing six epidermal growth factorlike repeats in the extracellular domain. Pref-1 is abundantly expressed in preadipocytes, but expression is down-regulated during adipocyte differentiation. Forced expression of Pref-1 in 3T3-L1 cells was reported to inhibit adipocyte differentiation. Here we show that efficient and regulated processing of Pref-1 occurs in 3T3-L1 preadipocytes releasing most of the extracellular domain as a 50-kDa heterogeneous protein, previously isolated and characterized as FA1. Unexpectedly, we found that forced expression of the soluble form, FA1, or full-length Pref-1 did not inhibit adipocyte differentiation of 3T3-L1 cells when differentiation was induced by standard treatment with methylisobutylxanthine, dexamethasone, and high concentrations of insulin. However, forced expression of either form of Pref-1/FA1 in 3T3-L1 or 3T3-F442A cells inhibited adipocyte differentiation when insulin or insulin-like growth factor-1 (IGF-1) was omitted from the differentiation mixture. We demonstrate that the level of the mature form of the IGF-1 receptor is reduced and that IGF-1-dependent activation of p42/p44 mitogen-activated protein kinases (MAPKs) is compromised in preadipocytes with forced expression of Pref-1. This is accompanied by suppression of clonal expansion and terminal differentiation. Accordingly, supplementation with insulin or IGF-1 rescued p42/p44 MAPK activation, clonal expansion, and adipocyte differentiation in a dose-dependent manner.

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“…Also, other signaling pathways have been demonstrated to be affected by the expression of Dlk1, e.g. mitogen-activated protein kinase (MAPK) (21) and insulin-like growth factor-I receptor-mediated p42/p44 MAPK activation (22). Despite this pleiotropic function of Dlk1 in many developmental and differentiation processes, little is known about the mechanisms mediating its regulatory function and its target genes.…”

mentioning

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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dlk Modulates Mitogen-Activated Protein Kinase Signaling to Allow or Prevent Differentiation

Cited by 48 publications

References 53 publications

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Insulin-like Growth Factor-1/Insulin Bypasses Pref-1/FA1-mediated Inhibition of Adipocyte Differentiation

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

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