Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice.

Soriano, Philippe

doi:10.1101/gad.8.16.1888

Cited by 893 publications

(660 citation statements)

References 44 publications

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“…Gleevec inhibits vascular endothelial growth factor expression indirectly through a PDGF inhibition-mediated mechanism (Wang et al, 1999). In addition, both PDGFR-b and PDGF-b null mutant mice die at late gestation from widespread microvascular bleeding (Leveen et al, 1994;Soriano, 1994). Taken together, we conclude from our data that signaling by at least one RTK III member is necessary for initiating or maintaining Int3 mammary tumorigenesis.…”

Section: Discussionsupporting

confidence: 58%

Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

et al. 2006

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Transgenic mice overexpressing Notch4 intracellular domain (Int3) under the control of the whey acidic protein (WAP) or mouse mammary tumor virus-long terminal repeat promoters, develop mammary tumors. Microarray analysis of these tumors revealed high levels of c-Kit expression. Gleevec is a tyrosine kinase inhibitor that targets c-Kit, platelet-derived growth factor receptors (PDGFRs) and c-Abl. This led us to speculate that tyrosine kinase receptor activity might be a driving force in the development of Int3 mammary tumors. WAP-Int3 tumor-bearing mice were treated with continuous release of Gleevec using subcutaneously implanted Alzet pumps. Phoshorylation of c-Kit, PDGFRs and c-Abl is inhibited in Int3 transgenic mammary tumors by Gleevec. Inhibition of these enzymes is associated with a decrease in cell proliferation and angiogenesis, and an induction of apoptosis. To examine the signaling mechanisms underlying Notch4/Int3 tumorigenesis, we employed small interfering RNA (siRNA) to knock down c-Kit, PDGFRs and c-Abl alone or in combination and observed the effects on soft agar growth of HC11 cells overexpressing Int3. Only siRNA constructs for c-Kit and/or PDGFR-a were able to inhibit HC11-Int3 colony formation in soft agar. Our data demonstrate an inhibitory effect of Gleevec on Int3-induced transformation of HC11 cells and mammary tumors and indicate an oncogenic role for c-Kit and PDGFR-a tyrosine kinases in the context of Int3 signaling.

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Section: Discussionsupporting

confidence: 58%

Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

et al. 2006

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“…We obtained wild-type, Pdgfra −/− and Pdgfrb −/− embryos from intercrosses of Pdgfra +/− or Pdgfrb +/− mice in a hybrid 129S4 × C57BL/6J genetic background and genotyped them as previously described 37,38 . We isolated primary MEFs from individual E12.5 embryos and maintained them in DMEM with 10% fetal calf serum, 50 U ml -1 penicillin and 50 µg ml -1 streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Identification and validation of PDGF transcriptional targets by microarray-coupled gene-trap mutagenesis

et al. 2004

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We developed a versatile, high-throughput genetic screening strategy by coupling gene mutagenesis and expression profiling technologies. Using a retroviral gene-trap vector optimized for efficient mutagenesis and cloning, we randomly disrupted genes in mouse embryonic stem (ES) cells and amplified them to construct a cDNA microarray. With this gene-trap array, we show that transcriptional target genes of platelet-derived growth factor (PDGF) can be efficiently and reliably identified in physiologically relevant cells and are immediately accessible to genetic studies to determine their in vivo roles and relative contributions to PDGF-regulated developmental processes. The same platform can be used to search for genes of specific biological relevance in a broad array of experimental settings, providing a fast track from gene identification to functional validation.

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“…6 Consistent evidence supporting a significant role in palatal development came from previous studies in Pdgfra knockout mice. [7][8][9][10] PDGFRa (MIM 173490) maps to chromosome 4q12, spans 65 kb, contains 23 exons, and encodes a protein with 743 amino-acid residues. PDGFRa has critical roles in mesenchymal cell migration and proliferation.…”

Section: Introductionmentioning

confidence: 99%

PDGFRa mutations in humans with isolated cleft palate

et al. 2012

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Isolated cleft palate (CP) is common in humans and has complex genetic etiologies. Many genes have been found to contribute to CP, but the full spectrum of genes remains unknown. PCR-sequencing of the entire coding regions and the 3 0 untranslated region (UTR) of the platelet-derived growth factor receptor alpha (PDGFRa) and the microRNA (miR), miR-140 identified seven novel single base-pair substitutions in the PDGFRa in 9/102 patients with CP (8.8%), compared with 5/500 ethnic-matched unaffected controls (1%) (the two-tailed P-valueo0.0001). Of these seven, four were missense mutations in the coding regions and three in the 3 0 UTR. Frequencies of four changes (three in coding, one in 3 0 UTR) were statistically different from those of controls (P-valueo0.05). The c.*34G4A was identified in 1/102 cases and 0/500 controls. This position is conserved in primates and located 10 bp away from a predicted binding site for the miR-140. Luciferase assay revealed that, in the presence of miR-140, the c.*34G4A significantly repressed luciferase activity compared with that of the wild type, suggesting functional significance of this variant. This is the first study providing evidence supporting a role of PDGFRa in human CP.

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Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice.

Cited by 893 publications

References 44 publications

Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

Identification and validation of PDGF transcriptional targets by microarray-coupled gene-trap mutagenesis

PDGFRa mutations in humans with isolated cleft palate

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