Disease relevance of Pdgfb

• This spectrum of pathological changes is reminiscent of diabetic microangiopathy, suggesting that the endothelium-restricted Pdgfb knockouts may serve as models for some of the pathogenic events of vascular complications to diabetes [1].
• Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice [2].
• Restriction fragment length variant analysis employing a mouse cDNA probe was used to localize the gene encoding murine activating transcription factor 4 (ATF-4) to mouse chromosome 15 in close proximity to Sis (the cellular homolog of the simian sarcoma virus oncoprotein) [3].
• Most PDGF B mutant embryos develop fatal hemorrhages just prior to birth [4].
• Long-term effects of lack of PDGF-B retention included severe retinal deterioration, glomerulosclerosis, and proteinuria [5].

High impact information on Pdgfb

• It has been proposed that platelet-derived growth factor B polypeptide (Pdgfb) secreted by these endothelial cells drives the formation of the surrounding muscular wall by recruiting nearby mesenchymal cells [6].
• We have previously shown that PDGF-B is required in the ontogeny of kidney mesangial cells [7].
• It is unusual among haemopoietic cell lines in that one of these is c-sis, the gene from which the oncogene v-sis of the simian sarcoma virus was derived, and perhaps the gene for platelet-derived growth factor (PDGF) [8].
• Pericyte loss and microaneurysm formation in PDGF-B-deficient mice [9].
• The gene encoding PDGF-B has given rise to the v-sis oncogene [10].

Chemical compound and disease context of Pdgfb

• These results indicated that PDGF-B overexpression can stimulate increased collagen deposition and vascular smooth muscle hyperplasia following asbestos inhalation and that a limited exposure (8 times) to chrysotile aerosol can produce long-lasting fibrotic lesions [11].
• In the present study we examined potential causes of this phenotypic variation and tested whether constitutive PDGF-B expression exacerbated fibrosis induced by bleomycin and silica [12].

Biological context of Pdgfb

• The IL-2 receptor beta chain gene (Il-2rb) is closely linked to the Pdgfb locus on mouse chromosome 15 [13].
• Here, we demonstrate that beta-PDGFR activation alone is sufficient for PDGF BB-mediated anchorage-independent cell growth [14].
• There were no structural changes in the PDGF-B gene, as determined by cytogenetic analysis and restriction mapping [15].
• Thus, TGF beta 1 has two roles in the growth of undifferentiated U9 colon carcinoma cells in vivo: direct stimulation of cell proliferation as we have showed in earlier studies, and an increase in angiogenesis by inducing PDGF-B [16].
• The mouse homolog (c-sis) of the transforming gene of the simian sarcoma virus was mapped to chromosome 15 by the Southern blot analysis of DNA's from hamster-mouse somatic cell hybrids [17].

Anatomical context of Pdgfb

• However, in marked contrast to the embryonic lethality of Pdgfb null mutants, the endothelium-specific mutants survived into adulthood with persistent pathological changes, including brain microhemorrhages, focal astrogliosis, and kidney glomerulus abnormalities [1].
• Here we demonstrate that transcription from a promoter containing NF-kappaB binding sequences as well as the DNA binding activity of NF-kappaB were increased in PDGF-B-chain-transformed mouse fibroblast cells [18].
• However, the PDGF-B gene in the NPA cells was hypomethylated compared to that in normal thyroid tissue or WRO cells [15].
• PDGF-B released from colon tumor cells regulated tumor growth in athymic mice in a paracrine manner by inducing blood vessel formation [16].
• TGF beta 1 was capable of inducing PDGF-B expression in the undifferentiated U9 colon carcinoma cell line, but this sensitivity was not seen in differentiated cells [16].

Associations of Pdgfb with chemical compounds

• Therefore, the transcription factor NF-kappaB plays a vital role in PDGF-B chain transformation of mouse fibroblast cells, and the NF-kappaB activity is sensitive to treatment with ASA [18].
• Focus formation of PDGF-B-chain-transformed mouse fibroblasts was suppressed by treatment with acetylsalicylic acid (ASA) and salicylic acid, which are known inhibitors of NF-kappaB activation, but other nonsteroidal anti-inflammatory drugs that do not have an effect on NF-kappaB activity did not affect focus formation in these cells [18].
• Moreover, cycloheximide superinduced IEGs and revealed PDGF-B transcripts, which were otherwise undetected [19].
• The cysteine mutant gene suppresses expression of PDGF-B (c-sis), as well as PDGF-A [20].
• Interestingly, PDGF-B-transformed NIH-3T3 cells are even more highly sensitized to TNF-induced cell death with PDGF-B inhibition [21].

Physical interactions of Pdgfb

• Furthermore, the stimulatory effects of TGF beta 1 on c-sis mRNA expression were shown to be pertussis-toxin sensitive and could be mimicked by direct activation of G-proteins with AIF4-. These results demonstrate that in AKR-2B cells a pertussis-toxin-sensitive guanine nucleotide regulatory protein(s) is coupled to TGF beta 1 receptor binding [22].
• Analysis of tyrosine-phosphorylated proteins demonstrated that Crk-associated substrate (p130(Cas)), not the activated PDGFbetaR itself, is the major Nck SH2 domain-binding protein in PDGF-B-stimulated cells [23].
• A 250-bp PDGF-B gene promoter attached to a reporter gene was shown to reproduce this TPA-induced activation [24].

Co-localisations of Pdgfb

• Furthermore, Nck and p130(Cas) colocalize in phosphotyrosine-enriched membrane ruffles induced by PDGF-B in NIH 3T3 cells [23].

Regulatory relationships of Pdgfb

• PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta1, suggesting a TGF-beta-independent mechanism [2].
• Membrane-anchored form of v-sis/PDGF-B induces mitogenesis without detectable PDGF receptor autophosphorylation [25].
• Expression of an ATP binding mutant of PKC-delta inhibits Sis-induced transformation of NIH3T3 cells [26].
• Functional studies confirmed the senescent dysregulation of TNF-alpha receptor pathways, demonstrating that TNF-alpha induced PDGF-B expression in cardiac microvascular endothelial cells of 4-mo-old, but not 24-mo-old, rats [27].
• Consistent with these in vitro findings, MT1-MMP-deficient brain tissues display a marked reduction in mural cell density as well as abnormal vessel wall morphology similar to that reported in mice expressing PDGF-B or PDGFRbeta hypomorphic alleles [28].

Other interactions of Pdgfb

• The results show that Mlvi -2 is present on mouse chromosome 15 but is unrelated to the c-myc and c-sis proto-oncogenes, which map on the same chromosome [29].
• Activation of NF-kappaB is required for PDGF-B chain to transform NIH3T3 cells [18].
• Analyses of alleles inherited as passengers in B6.C-H-30c, C3H.B-Ly-6b, and C57BL/6By-Eh/+ congenic mouse strains and in situ hybridization experiments support the above gene order and indicate further that the cluster is located on distal chromosome 15, with Ly-6 and Sis near Eh [30].
• Three of these loci, Sis, Int-1, and Gdc-1, have been previously mapped to chromosome 15 by others using somatic cell hybrids or isoenzyme analyses [30].
• Composite interval mapping (CIM) analysis indicated that there was a significant association between loci at Pdgfb and D2Mit74 in both males and females [31].

Analytical, diagnostic and therapeutic context of Pdgfb

• To address the role of PDGF-B retention in vivo, we deleted the retention motif by gene targeting in mice [5].
• Expression of platelet-derived growth factor (PDGF)-A and PDGF-B is increased in patients with proliferative retinopathies in which traction retinal detachments occur [32].
• Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes [33].
• Using cDNA microarrays, we analyzed the gene expression in PDGF-B null embryos in comparison with corresponding wild-type embryos and searched for down-regulated genes [34].
• We used site-directed mutagenesis to determine the minimum number of PDGF B residues needed to convert PDGF A to a potently transforming PDGF B-like molecule [35].

References