Disease relevance of DLK1

• Imprinted DLK1 is a putative tumor suppressor gene and inactivated by epimutation at the region upstream of GTL2 in human renal cell carcinoma [1].
• In order to see the biological significance of DLK1 inactivation in RCCs, we tested the effect of restoration of DLK1 in RCC cell lines, using a recombinant retrovirus containing the gene [1].
• This study found that the expression of DLK1 in gliomas was higher than that in normal brain (P < 0.05) [2].
• The Delta-like (DLK1) gene is overexpressed in CD34+ cells from myelodysplastic syndrome (MDS) patients [3].
• DLK1-enriched condition medium stimulated the growth of glioblastoma multiforme cell lines and explants [2].

High impact information on DLK1

• Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12 [4].
• This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates [5].
• Moreover, constitutive expression of pref-1 in preadipocytes, which in effect blocks its down-regulation, drastically inhibits adipose differentiation [5].
• In preadipocytes, multiple discrete forms of pref-1 protein of 45-60 kd are present, owing in part to N-linked glycosylation [5].
• Directional selectivity is a response that is greater for a visual stimulus moving in one (PREF) direction than for the opposite (NULL) direction, and its computation in the vertebrate retina is a classical issue in functional neurophysiology [6].

Chemical compound and disease context of DLK1

• The expression of both pG8 and pG2 can be induced in human neuroblastoma cells with dexamethasone, suggesting a mechanism by which glucocorticoids may influence development of a neuroendocrine phenotype [7].
• Homology modeling and S(N)2 displacement reaction of fluoroacetate dehalogenase from Burkholderia sp. FA1 [8].

Biological context of DLK1

• To explore the role of epigenetic regulation of DLK1 inactivation in RCCs, we conducted methylation analysis of the upstream region and the gene body of DLK1 [1].
• Reintroduction of DLK1 into DLK1-null RCC cell lines markedly increased anchorage-independent cell death, anoikis and suppressed tumor growth in nude mice [1].
• The paternal expression, chromosomal localization, and biological function of DLK1 also make it a likely candidate gene for the callipyge phenotype in sheep [9].
• Furthermore, in vitro differentiation of the uninduced blastema leads to rapid down-regulation of PEG3, DLK1, and MEIS1 [10].
• Here we report the identification of two reciprocally imprinted genes, GTL2 and DLK1, which together define a novel imprinting cluster on human chromosome 14q32 [9].

Anatomical context of DLK1

• We report that imprinted DLK1 at 14q32, a regulator of adipocyte differentiation, is a candidate TSG in RCCs [1].
• DLK1 was expressed in only one of 15 (7%) RCC-derived cell lines [1].
• We show that ectopically expressed DLK1 significantly inhibits differentiation and proliferation of human promyelocytic HL-60 cells [3].
• Immunohistochemical analysis of DLK1 was performed on 13 tumours and two intralobar nephrogenic rests, in addition to two fetal kidneys and one fetal skeletal muscle sample [11].
• Neurons in the monoaminergic nuclei of the rat and human central nervous system express FA1/dlk [12].

Associations of DLK1 with chemical compounds

• However, a direct effect of octreotide on FA1 levels, independent of GH levels, has not been ruled out [13].
• The FA1 responses to placebo were not significantly different from the responses to the combination of pyridostigmine and GHRH [13].
• Fetal antigen 1 (FA1) is a glycoprotein containing six epidermal growth factor (EGF)-like repeats [14].
• Using cyclic AMP and RA in combination, we found that RA inhibited expression of adrenal gland specific gene pG2 and induced a neuronal phenotype [15].
• Our results show that the adrenal gland specific gene pG2 is induced only during dbcAMP treatment, while RA induces a neuronal phenotype and expression of all neural related genes while decreasing the expression of many chromaffin related genes [15].

Regulatory relationships of DLK1

• Protein structure of fetal antigen 1 (FA1). A novel circulating human epidermal-growth-factor-like protein expressed in neuroendocrine tumors and its relation to the gene products of dlk and pG2 [16].

Other interactions of DLK1

• These data show that imprinting of DLK1 is maintained in brain tumors and lymphomas, even though the DLK1 gene is very analogous to the IGF2 gene in its DNA structure and regulation [17].
• The present data have shown that gain of methylation upstream of the untranslated GTL2 leads to pathological downregulation of DLK1 in RCCs [1].
• DLK1 expression in Wilms tumour might reflect the presence of myogenic differentiation, rather than an alteration of its imprinting status [11].
• The question arises as to whether DLK1 also undergoes LOI in Wilms tumour, or whether the LOI mechanism is restricted to the H19/IGF2 domain [11].
• Expression of DLK1 in hematopoietic cells results in inhibition of differentiation and proliferation [3].

Analytical, diagnostic and therapeutic context of DLK1

• In addition to pituitary adenomas, various endocrine tumors were subjected to real-time-quantitative PCR revealing high expression of DLK1 in normal pituitary tissue, in GH-S-, in one prolactin-secreting pituitary adenoma and in pheochromocytomas [18].
• In a gene chip analysis of common pituitary tumor types, one of the genes with the most impressive tissue-specific expression regulation was delta-like 1 (DLK1), which was strongly expressed in GH-secreting (GH-S) pituitary tumors [18].
• Assignment of DLK1 to human chromosome band 14q32 by in situ hybridization [19].
• Northern blot analysis confirmed high DLK1 expression in SK-N-FI and several other neuroblastoma cell lines [20].
• Ex vivo calvaria organ cultures assay was used to confirm the in vitro effect of Dlk/Pref-1 on bone formation [21].

References