Role of HB-GAM (Heparin-Binding Growth-Associated Molecule) in Proliferation Arrest in Cells of the Developing Rat Limb and Its Expression in the Differentiating Neuromuscular System

Szabat, Ewa; Rauvala, Heikki

doi:10.1006/dbio.1996.0199

Cited by 40 publications

(23 citation statements)

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“…We have listed Ptn as a neuronal marker as it is expressed in specific areas of the developing and adult nervous system (49), Ptn-deficient mice exhibit neurophysiologic and behavioral phenotypes (50,51), and it is thought to affect the proliferation and differentiation of particular neuronal cell types (52,53). However, Ptn has also been proposed to play important roles in bone physiology, specifically as a positive regulator of both osteoblast differentiation and function (54,55).…”

Section: Discussionmentioning

confidence: 99%

Dominant-Stable β-Catenin Expression Causes Cell Fate Alterations and Wnt Signaling Antagonist Expression in a Murine Granulosa Cell Tumor Model

Boerboom¹,

White

Dalle

et al. 2006

Cancer Research

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Wnt/B-catenin signaling is normally involved in embryonic development and tissue homeostasis, and its misregulation leads to several forms of cancer. We have reported that misregulated Wnt/B-catenin signaling occurs in ovarian granulosa cell tumors (GCT) and have created the Catnb flox(ex3)/+ ; Amhr2 cre/+ mouse model, which expresses a dominant-stable mutant of B-catenin in granulosa cells and develops late-onset GCT. To study the mechanisms leading to GCT development, gene expression analysis was done using microarrays comparing Catnb flox(ex3)/+ ; Amhr2 cre/+ ovaries bearing pretumoral lesions with control ovaries. Overexpressed genes identified in Catnb flox(ex3)/+ ; Amhr2 cre/+ ovaries included the Wnt/B-catenin signaling antagonists Wif1, Nkd1, Dkk4, and Axin2, consistent with the induction of negative feedback loops that counteract uncontrolled Wnt/B-catenin signaling. Expression of the antagonists was localized to cells forming the pretumoral lesions but not to normal granulosa cells. Microarray analyses also revealed the ectopic expression of bone markers, including Ibsp, Cdkn1c, Bmp4, and Tnfrsf11b, as well as neuronal/neurosecretory cell markers, such as Cck, Amph, Pitx1, and Sp5. Increased expression of the gene encoding the cytokine pleiotrophin was also found in Catnb flox(ex3)/+ ; Amhr2 cre/+ ovaries and GCT but was not associated with increased serum pleiotrophin levels. In situ hybridization analyses using GCT from Catnb flox(ex3)/+ ; Amhr2 cre/+ mice revealed that Wnt/B-catenin antagonists and neuronal markers localized to a particular cell population, whereas the bone markers localized to a distinct cell type associated with areas of osseous metaplasia. Together, these results suggest that misregulated Wnt/B-catenin signaling alters the fate of granulosa cells and that the GCT that arise in Catnb flox(ex3)/+ ; Amhr2 cre/+ mice result from the clonal expansion of metaplastic cells. (Cancer Res 2006; 66(4): 1964-73)

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Section: Discussionmentioning

confidence: 99%

Dominant-Stable β-Catenin Expression Causes Cell Fate Alterations and Wnt Signaling Antagonist Expression in a Murine Granulosa Cell Tumor Model

Boerboom¹,

White

Dalle

et al. 2006

Cancer Research

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“…Ptn (also named Osf1, HB-GAM, HBGF-8 and HBNF) has previously been reported to negatively regulate cell proliferation in rat limb buds (Szabat and Rauvala, 1996) and was upregulated in the growth-retarded Twist Ϫ/Ϫ forelimb. Several other clones showed homology to highly abundant retroviral or transposable element-related sequences.…”

Section: Identification Of Subtracted Clonesmentioning

confidence: 99%

Isolation of differentially expressed genes from wild‐type and Twist mutant mouse limb buds

Loebel

O'Rourke

Steiner

et al. 2002

Genesis

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In the mouse, Twist is required for normal limb and craniofacial development. We show that the aristaless-like transcription factors, Alx3 and Alx4 are downregulated in the Twist(-/-) mutant and may be potential targets of Twist. By suppression subtractive hybridization we isolated 31 and 18 unique clones representing mRNAs that are putatively downregulated and upregulated respectively in Twist(-/-) forelimb buds. These included genes encoding cytoskeletal components, metabolic enzymes, hemoglobin molecules, membrane transport proteins, components of transcription and translation complexes, protein modification enzymes and proteins related to cell proliferation and apoptosis. Differential expression of selected clones was validated by whole mount in situ hybridization to E10.5 wild-type and Twist(-/-) embryos. We show that four novel clones are expressed in the Twist-expressing craniofacial tissues and paraxial mesoderm and downregulated in Twist(-/-) embryos, raising the possibility that they are, in addition to genes of the Alx family, downstream targets of Twist.

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“…Failure to express this factor would allow the oncogenically transformed cells to continue to proliferate without regard to cell-cell contact. A very recent report lends some support to this hypothesis by showing that pleiotrophin can inhibit the proliferation of mesenchymal and epithelial cells in cultured rat limb buds (56). The increase in pleiotrophin expression by confluent cells in response to serum (this paper) or to platelet-derived growth factor (57) might then be a signal to reinforce the quiescence by blocking the response of the cells to an increased concentration of mitogens.…”

Section: Discussionmentioning

confidence: 74%

Transformation by Ras Suppresses Expression of the Neurotrophic Growth Factor Pleiotrophin

Corbley

1997

Journal of Biological Chemistry

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An 18-kDa protein (p18) was detected in lysates and conditioned medium from contact-arrested NIH 3T3 fibroblasts, but was not detected when the cells were transformed by the oncogene ras. Analysis of transformation-defective cell clones generated after mutagenesis of the ras-retroviral vector used to transduce the ras gene showed an inverse correlation between p18 expression and the degree of transformation. p18 expression was high in non-transformed clones, intermediate in a partially transformed clone, undetectable in fully transformed clones, and detectable only at the non-permissive temperature in a clone which was cold-sensitive for ras transformation. In non-transformed cells, p18 expression varied with the degree of confluence. It was almost undetectable in medium from sparse, proliferating cells, but increased as the cells approached confluence and peaked 2-4 days after confluence. Microsequencing of partially purified p18 identified it as the developmentally regulated neurotrophic factor pleiotrophin. In further experiments, pleiotrophin was undetectable or almost undetectable in medium from fully transformed cells expressing the oncogenes v-src, truncated c-raf, activated c-fms, or polyomavirus middle tumor antigen; it was low but easily detectable in medium from SV40 large tumor antigen-expressing cells, which form soft agar colonies but not foci. Thus, pleiotrophin expression in NIH 3T3 cells is associated with quiescence, and suppression of pleiotrophin is related to oncogenic transformation.

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Role of HB-GAM (Heparin-Binding Growth-Associated Molecule) in Proliferation Arrest in Cells of the Developing Rat Limb and Its Expression in the Differentiating Neuromuscular System

Cited by 40 publications

References 0 publications

Dominant-Stable β-Catenin Expression Causes Cell Fate Alterations and Wnt Signaling Antagonist Expression in a Murine Granulosa Cell Tumor Model

Dominant-Stable β-Catenin Expression Causes Cell Fate Alterations and Wnt Signaling Antagonist Expression in a Murine Granulosa Cell Tumor Model

Isolation of differentially expressed genes from wild‐type and Twist mutant mouse limb buds

Transformation by Ras Suppresses Expression of the Neurotrophic Growth Factor Pleiotrophin

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