Constitutive notch signaling in adult transgenic mice inhibits bFGF‐induced angiogenesis and blocks ovarian follicle development

Liu, Ju; Deutsch, Urban; Jeong, James; Lobe, Corrinne G.

doi:10.1002/dvg.22790

Cited by 18 publications

(17 citation statements)

References 30 publications

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“…no Zeg-ic-notch1/tie2-cre positive offspring were obtained, and we found that the double transgenic embryos died before e10.5 with defects in vascular development and widespread hemorrhaging. these observations were consistent with our previous studies showing the lethality of Zeg-ic-notch1/tie2-cre embryos with lack of angiogenic remodeling and branching in the yolk sacs and embryonic bodies (24,25). In these IC-Notch1 expressing embryos, the circulation system of hematopoietic cells have been developed before the death of the embryos.…”

Section: Zeg-ic-notch1supporting

confidence: 93%

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Postnatal Notch1 activation induces T-cell malignancy in conditional and inducible mouse models

Liu

Fang

Fung

et al. 2014

International Journal of Oncology

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Abstract. the notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEG-IC-Notch1 transgenic mice that have a floxed β-geo/stop signal between a cMV promoter and intracellular domain of notch1 (ic-notch1). constitutively active ic-notch1 is silent until the introduction of cre recombinase. in this study, endothelial/hematopoietic specific expression of IC-Notch1 in double transgenic Zeg-ic-notch1/tie2-cre embryos induced embryonic lethality at e9.5 with defects in vascular system but not in hematopoietic system. Inducible IC-Notch1 expression in adult mice was achieved by using tetracycline regulated cre system. the Zeg-ic-notch1/tie2-tta/tet-o-cre triple transgenic mice survived embryonic development when maintained on tetracycline. Post-natal withdrawal of tetracycline induced expression of IC-Notch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive T-cell infiltration in multiple organs and T-cell malignancy of lymph nodes. in addition, the protein levels of p53 and alternative reading frame (arf) were decreased in lymphoma-like neoplasms from the triple transgenic mice while their mrna expression remained unchanged, suggesting that IC-Notch1 might repress arf-p53 pathway by a post-transcriptional mechanism. this study demonstrated that activation of constitutive notch1 signaling after embryonic development alters adult hematopoiesis and induces t-cell malignancy. Introductionnotch is a family of highly conserved cell-surface receptors that are required in many mammalian developmental processes (1). the interaction of notch receptors and its ligands initiates a cascade of proteolytic cleavages. tnf-α converting enzyme, a metalloprotease, cleaves the extracellular subunit to leave membrane-bound form of the transmembrane subunit of notch receptors. Then a presenilin-associated multiprotein complex with γ-secretase activity recognizes and cleaves a site within the transmembrane domain to release the intracellular domain of notch (ic-notch). ic-notch translocates to the nucleus and converts the transcription factor cBf1/Su(H)/lag1 (cSl) from a repressor to a transcriptional activator (2). the downstream targets of notch/cSl include Hairy-enhancer of split (HeS) and Hes-related protein (HerP/Hey) families, which function as transcriptional repressors suppressing the expression of cell type specific target genes (3).to date, four notch receptors (notch 1-4) and five ligands (δ-like 1, 2 and 4; jagged 1 and 2) have been described in mammals (2). Notch1 is expressed in most embryonic and adult tissues. Notch1 protein has an extracellular domain consisting of multiple egf-like repeats and three cysteine-rich lin12 repeats with heterodimerization (HD) domain, a transmembrane domain and intracellular domain containing a CSL associating motif domain, six ankyrin repeats, nuclear localization signals (nlS), a glutamine-ric...

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Section: Zeg-ic-notch1supporting

confidence: 93%

“…in spleen, the proportion of gfP positive cells ranges from 12-70%. Mosaic expression was also observed in endothelial cells of the triple transgenic mice (25).…”

Section: Ic-notch1 Expression Was Activated In Hematopoietic Cellsmentioning

confidence: 80%

Postnatal Notch1 activation induces T-cell malignancy in conditional and inducible mouse models

Liu

Fang

Fung

et al. 2014

International Journal of Oncology

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“…The role of Notch signaling within the ovarian vasculature of mice has also been examined using a gain-of-function genetic model (Liu et al 2014). Constitutive activation of the Notch pathway in vascular endothelial cells by induction of NICD1 expression under the control of a tamoxifen-inducible Tie2 - Cre allele results in severely altered female fertility, and ovaries from these mice lack mature ovarian follicles.…”

Section: Notch Pathway In the Ovarian Vasculaturementioning

confidence: 99%

The role of Notch signaling in the mammalian ovary

Vanorny

Mayo

2017

Reproduction

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The Notch pathway is a contact-dependent, or juxtacrine, signaling system that is conserved in metazoan organisms and is important in many developmental processes. Recent investigations have demonstrated that the Notch pathway is active in both the embryonic and postnatal ovary and plays important roles in events including follicle assembly and growth, meiotic maturation, ovarian vasculogenesis, and steroid hormone production. Ovarian pathologies resulting from disruption of the Notch pathway in mice affect meiotic spindle assembly, follicle histogenesis, granulosa cell proliferation and survival, corpora luteal function, and ovarian neovascularization. These aberrations result in abnormal folliculogenesis and reduced fertility. Knowledge of the cellular interactions facilitated by the Notch pathway is an important area for continuing research and future studies are expected to enhance our understanding of ovarian function and provide critical insights for improving reproductive health. This review focuses on the expression of Notch pathway components in the ovary, and on the multiple functions of Notch signaling in follicle assembly, maturation, and development. We focus on the mouse, where genetic investigations are possible, and relate this information to the human ovary.

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“…In particular, tumor angiogenesis is crucial for solid tumor growth, invasion and metastasis (4). During tumor growth, the production of angiogenic factors, including members of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) families, from tumor cells results in the induction of capillary spouting and the subsequent growth of novel vessels in tumors from surrounding host vessels (3,5). As the vessels in the tumor are tortuous, with sluggish flow and a lack of surrounding pericytes, tumor cells readily invade into novel vessels and form tumor emboli (3).…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin induces endothelial cell anoikis through the activation of the JNK signaling pathway

et al. 2016

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Angiogenesis is required for the growth and metastasis of solid tumors. The anti-malarial agent dihydroartemisinin (DHA) demonstrates potent anti-angiogenic activity, but the underlying molecular mechanisms are not yet fully understood. During the process of angiogenesis, endothelial cells migrating from existing capillaries may undergo programmed cell death after detaching from the extracellular matrix, a process that is defined as anchorage-dependent apoptosis or anoikis. In the present study, DHA-induced cell death was compared in human umbilical vein endothelial cells (HUVECs) cultured in suspension and attached to culture plates. In suspended HUVECs, the cell viability was decreased and apoptosis was increased with the treatment of 50 µM DHA for 5 h, while the same treatment did not affect the attached HUVECs. In addition, 50 µM DHA increased the phosphorylation of c-Jun N-terminal kinase (JNK) in suspended HUVECs, but not in attached HUVECs, for up to 5 h of treatment. The JNK inhibitor, SP600125, reversed DHA-induced cell death in suspended HUVECs, suggesting that the JNK pathway may mediate DHA-induced endothelial cell anoikis. The data from the present study indicates a novel mechanism for understanding the anti-angiogenic effects of DHA, which may be used as a component for chemotherapy.

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Constitutive notch signaling in adult transgenic mice inhibits bFGF‐induced angiogenesis and blocks ovarian follicle development

Cited by 18 publications

References 30 publications

Postnatal Notch1 activation induces T-cell malignancy in conditional and inducible mouse models

Postnatal Notch1 activation induces T-cell malignancy in conditional and inducible mouse models

The role of Notch signaling in the mammalian ovary

Dihydroartemisinin induces endothelial cell anoikis through the activation of the JNK signaling pathway

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