Identification of DLK1 variants in pituitary- and neuroendocrine tumors

Altenberger, T; Bilban, Martin; Auer, Michael; Knosp, Engelbert; Wolfsberger, Stefan; Gärtner, Wolfgang; Mineva, I.; Zielinski, C. C.; Wagner, Ludwig; Luger, Anton

doi:10.1016/j.bbrc.2005.12.094

Cited by 27 publications

(22 citation statements)

References 40 publications

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“…After separating the tumors into the clinical subtypes (NFAs, GH-S, ACTH-S), the NFAs showed more differentially expressed genes compared with the functional tumors (876 vs. 377, respectively) consistent with a previous study (27).…”

Section: Microarraysupporting

confidence: 74%

Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors

et al. 2007

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Section: Microarraysupporting

confidence: 74%

Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors

et al. 2007

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“…The function of these genes is still unknown, although for Dlk1, it has become clear that this gene is over expressed in brain tumors. 44,45 None of these genes have ever been related to anxiety, but the results of the studies in mice together with our results indicate that it may be worthwhile to investigate the association. A further search did not reveal other genes under this peak that have been related to symptoms of anxiety.…”

Section: Discussionmentioning

confidence: 57%

Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype

et al. 2007

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Several linkage studies on anxiety have been carried out in samples ascertained through probands with panic disorder. The results indicated that using a broad anxiety phenotype instead of a DSM-IV anxiety disorder diagnosis might enhance the chance of finding a linkage signal. In the current study, a genome-wide linkage analysis was performed on anxiety measured with a self-report questionnaire whose scores are highly correlated with DSM-IV anxiety disorders. The self-report questionnaire was included in five surveys of a longitudinal study of the Netherlands Twin Register. Genotype and phenotype data were available for 1602 twins and siblings. To estimate identity by descent , additional genotype data for 564 parents and 22 siblings were used. Linkage analyses were carried out using MERLIN-regress on the average anxiety scores across time. A linkage signal (logarithm of odds score 3.4, empirical P-value 0.07) was obtained at chromosome 14 for marker D14S65 at 105 cM (90% confidence interval, 99-115 cM bounded by markers D14S1434 and D14S985). This finding replicates a linkage finding for a broad anxiety phenotype in a clinically based sample, indicating that the region might harbor a quantitative trait locus associated with the whole spectrum of general anxiety, that is from the normal to the clinical range. Moreover, genome-wide linkage and association studies on emotionality in mice obtained significant results in a syntenic region on mouse chromosome 12. Two homolog genes lie in this region -Dlk1 (delta-like 1 homolog, Drosophila) and Rtl1 (retrotransposon-like 1). Future association studies of these genes are warranted.

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“…Dlk1 is expressed in the normal pituitary gland [31,32], specifically in the GH -producing somatotroph cells [16,33]. Dlk1 is also expressed in pancreatic β cells [17], leydig cells and the theca interna and Hilus cells of the ovary [18], suggesting that Dlk1 has endocrine-related functions.…”

Section: Discussionmentioning

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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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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Identification of DLK1 variants in pituitary- and neuroendocrine tumors

Cited by 27 publications

References 40 publications

Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors

Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors

Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype

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

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