Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth.
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Amino Acid Sequence↗
Biomedical subjects
L Holmgren
Publications and source records attributed to L Holmgren.
Overlapping patterns of IGF2 and H19 expression during human development: biallelic IGF2 expression correlates with a lack of H19 expression.
The spatial patterns of IGF2 and H19 gene expression are strikingly similar during parts of human embryonic/fetal and early postnatal development. Notable exceptions were found with the ciliary anlage of the embryonic retina and the choroid plexus/leptomeninges, where transcripts from the IGF2 but not the H19 locus could be detected. Moreover, in contrast to the other tissue samples examined, the choroid plexus/leptomeninges expressed both parental IGF2 alleles. Whilst RNase protection analysis revealed a weak activity of the P1 promoter in the choroid plexus/leptomeninges, the P2, P3 and P4 promoters were all active wherever IGF2 was expressed. We discuss these observations with respect to a hypothesized coordinated control of the reciprocally imprinted and closely linked IGF2 and H19 loci.
Alleles↗
The cell type-specific IGF2 expression during early human development correlates to the pattern of overgrowth and neoplasia in the Beckwith-Wiedemann syndrome.
Overstimulation by insulin-like growth factor II is implied in several overgrowth conditions and childhood cancers. We have therefore studied spatial and temporal expression patterns of the insulin-like growth factor II gene (IGF2) and the insulin-like growth factor type 1 receptor gene during normal human development (5.5 to 23.0 weeks postfertilization). The set of cell types with the most abundant IGF2 expression correlated strikingly to the organomegaly and tumor predisposition of the Beckwith-Wiedemann syndrome. Intrauterine growth and postnatal organ weights of a prematurely born child with a full-blown syndrome are presented. The cell type-specific IGF2 expression of these organs and of multifocal Wilms' tumors from two other children affected by the Beckwith-Wiedemann syndrome were also studied. The results clarify and extend previous findings concerning human prenatal IGF2 expression and are consistent with a short range overstimulatory role of locally produced IGF II ensuing after the first trimester in the Beckwith-Wiedemann syndrome.
Beckwith-Wiedemann Syndrome↗
Successive activation of the platelet-derived growth factor beta receptor and platelet-derived growth factor B genes correlates with the genesis of human choriocarcinoma.
The hydatidiform mole is a benign disease of the placenta characterized by the absence of the maternal genome. Approximately 3% of the reported cases will develop into malignant choriocarcinoma. In situ hybridization analysis reveals that the paternal platelet-derived growth factor (PDGF) beta receptor gene is up to 2 orders of magnitude more active in cytotrophoblasts of the complete hydatidiform moles than in normal placentae. The transition between hyperplasia (complete hydatidiform mole) and neoplasia (choriocarcinoma) in these cells correlates with at least a 10- to 20-fold activation of the PDGF-B gene. Since the neoplastic cytotrophoblasts have maintained an abnormally high level of PDGF beta receptor expression, we propose that a deregulated PDGF autostimulatory loop is involved in the genesis of human choriocarcinoma from hydatidiform moles.
Choriocarcinoma↗
The expression of PDGF alpha- and beta-receptors in subpopulations of PDGF-producing cells implicates autocrine stimulatory loops in the control of proliferation in cytotrophoblasts that have invaded the maternal endometrium.
In order to explain the high proliferative potential of human placental cytotrophoblasts, we have addressed the potential involvement of platelet-derived growth factor (PDGF) ligand and receptors. Although PDGF is usually described as a mitogen for cells of mesenchymal origin, we show in this report that extra-villous term placental cytotrophoblasts express the PDGF alpha- and beta-receptor genes, both in vivo and in vitro. In addition, cytotrophoblasts produce significant amounts of PDGF-B protein. By immunohistochemical analysis of receptor expression, we found that the PDGF alpha-receptors could be detected at the cell surface, while the PDGF beta-receptors were only detected intracellularly. In addition, double immunostaining analysis showed that the PDGF alpha- and beta-receptor molecules are expressed in different subpopulations of cytotrophoblasts. The addition of PDGF-AA and PDGF-BB homodimers to cytotrophoblast primary cultures induced a significant increase in DNA synthesis. We conclude, therefore, that PDGF is a growth factor for placental cytotrophoblasts and suggest that the growth of cytotrophoblasts can partly be explained by a PDGF autostimulatory loop, limited by the number of receptor-positive cytotrophoblasts.
Cell Membrane↗
Expression of the human PDGF-B gene is regulated by both positively and negatively acting cell type-specific regulatory elements located in the first intron.
Potential cis-acting regulatory elements of the human platelet derived growth factor-B (PDGF-B) gene were identified by DNase I hypersensitive site mapping. The transcription unit was examined for the presence of hypersensitive sites in chromatin DNA isolated from human term placental cytotrophoblasts, human placental fibroblasts, the JEG-3 choriocarcinoma cell line and the U2-OS osteosarcoma cell line. A number of cell type-specific hypersensitive sites were identified, all within the 1st intron. Transient transfection of JEG-3 cells with CAT constructs containing regions of the c-sis 1st intron linked to the basal c-sis promoter identified a cell type-specific positive regulatory activity within the intron, composed of at least two distinct elements. One element appeared to be specific for JEG-3 cells, while the other was also active in U2-OS cells. The overall positive regulatory activity of the 1st intron region was specific for JEG-3 cells, but did not function as a classically defined enhancer, as it was orientation-dependent (unless stably integrated into chromatin DNA). In addition, the activator appears to require interaction with the c-sis promoter, as little or no activation was seen when either the SV40 or human beta-globin promoters were substituted for the c-sis promoter. The 1st intron also contained a negative regulatory element, which was specific for U2-OS cells and silenced an abnormally high basal c-sis promoter activity in these cells. The complexity of the transcriptional control of the PDGF-B gene is discussed.
Base Sequence↗
Angiogenesis during human extraembryonic development involves the spatiotemporal control of PDGF ligand and receptor gene expression.
We have examined the role of platelet-derived growth factor (PDGF) ligand and receptor genes in the angiogenic process of the developing human placenta. In situ hybridization analysis of first trimester placentae showed that most microcapillary endothelial cells coexpress the PDGF-B and PDGF beta-receptor genes. This observation indicates that PDGF-B may participate in placental angiogenesis by forming autostimulatory loops in capillary endothelial cells to promote cell proliferation. Endothelial cells of macro blood vessels maintained high PDGF-B expression, whereas PDGF beta-receptor mRNA was not detectable. In contrast, PDGF beta-receptor mRNA was readily detectable in fibroblast-like cells and smooth muscle cells in the surrounding intima of intermediate and macro blood vessels. Taken together, these data suggest that the PDGF-B signalling pathway appears to switch from an autocrine to a paracrine mechanism to stimulate growth of surrounding PDGF beta-receptor-positive mesenchymal stromal cells. Smooth muscle cells of the blood vessel intima also expressed the PDGF-A gene, the protein product of which is presumably targeted to the fibroblast-like cells of the mesenchymal stroma as these cells were the only ones expressing the PDGF alpha-receptor. PDGF-A expression was also detected in columnar cytotrophoblasts where it may have a potential role in stimulating mesenchymal cell growth at the base of the growing placental villi. We discuss the possibility that the regulation of the PDGF-B and beta-receptor gene expression might represent the potential targets for primary angiogenic factors.
Blotting, Northern↗
Cellular localization of cytochrome(s) P-450 metabolizing polycyclic aromatic hydrocarbons in the rat adrenal cortex.
Cells were dispersed from the capsular, as well as the inner portion of female rat adrenal glands and subsequently separated on discontinuous Percoll gradients. The adrenal cells were distributed within a density interval ranging from 1.016 to 1.075 g/cm3 and different subpopulations showed distinct morphological appearances in suspension, as well as in culture. The total cells from the inner portion of the adrenals metabolized [14C]7,12-dimethylbenz(a)anthracene at a rate of 4.04 pmol/min 10(6) cells and synthesized corticosterone in response to ACTH stimulation at a rate of 1.07 micrograms/hr/10(6) cells. These activities were 4- and 2.5-fold higher, respectively, than the corresponding activities in cells isolated from the capsular portion. 7,12-Dimethylbenz(a)anthracene monoxygenase activity and ACTH-stimulated steroidogenesis were enriched in two subpopulations of cells obtained on the Percoll gradient and were estimated to be 13.1 pmol/min/10(6) cells and 3.21 micrograms/hr/10(6) cells, respectively, in the most active fraction (at the 1.034/1.040 g/cm3 interface). On the basis of cellular morphology, density and steroidogenic properties, it was concluded that adrenal 7,12-dimethylbenz(a)anthracene monoxygenase activity is localized mainly in the cells of the zona fasciculata.
9,10-Dimethyl-1,2-benzanthracene↗
Insulin-like growth factor 2 and short-range stimulatory loops in control of human placental growth.
Substructures of the first-trimester human placenta (within 3 months post-conception) display 'pseudo-malignant' properties. We show here, by in situ hybridization, that the insulin-like growth factor 2 (IGF-2) gene expression is particularly active in the cytotrophoblasts, which dominate these structures. Because the majority of placental IGF-2 mRNA is polysomal in extracts of first-trimester placenta, the spatial pattern of IGF-2 transcripts generally also defines the pattern of IGF-2 production. In primary trophoblast cultures, rendered quiescent by serum starvation. IGF-2 performs as a human embryonic growth factor by activating cell cycle entry/progression. Although both type 1 and 2 IGF receptor mRNAs can be found co-distributed with IGF-2 mRNA during placental development (supporting an autocrine role for IGF-2), these occasional patterns are confined to cytotrophoblasts with low proliferative potential. The reciprocity in ligand and receptor expression patterns are discussed in terms of rate-limiting steps in the involvement of IGF-2 in the proliferative phenotype of the early human placenta.
Cell Division↗
[Hearing aid prescription and adjustment in Sweden].
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Audiometry↗