文章基本信息

标题：Altered regulation of platelet-derived growth factor receptor-α gene-transcription in vitro by spina bifida-associated mutant Pax1 proteins
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作者：Paul H. L. J. Joosten ; Frans A. Hol ; Sylvia E. C. van Beersum 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：24
页码：14459-14463
DOI：10.1073/pnas.95.24.14459
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Mouse models show that congenital neural tube defects (NTDs) can occur as a result of mutations in the platelet-derived growth factor receptor- gene (PDGFR). Mice heterozygous for the PDGFR-mutation Patch, and at the same time homozygous for the undulated mutation in the Pax1 gene, exhibit a high incidence of lumbar spina bifida occulta, suggesting a functional relation between PDGFR and Pax1. Using the human PDGFR promoter linked to a luciferase reporter, we show in the present paper that Pax1 acts as a transcriptional activator of the PDGFR gene in differentiated Tera-2 human embryonal carcinoma cells. Two mutant Pax1 proteins carrying either the undulated-mutation or the Gln [->] His mutation previously identified by us in the PAX1 gene of a patient with spina bifida, were not or less effective, respectively. Surprisingly, Pax1 mutant proteins appear to have opposing transcriptional activities in undifferentiated Tera-2 cells as well as in the U-2 OS osteosarcoma cell line. In these cells, the mutant Pax1 proteins enhance PDGFR-promoter activity whereas the wild-type protein does not. The apparent up-regulation of PDGFR expression in these cells clearly demonstrates a gain-of-function phenomenon associated with mutations in Pax genes. The altered transcriptional activation properties correlate with altered protein-DNA interaction in band-shift assays. Our data provide additional evidence that mutations in Pax1 can act as a risk factor for NTDs and suggest that the PDGFR gene is a direct target of Pax1. In addition, the results support the hypothesis that deregulated PDGFR expression may be causally related to NTDs.
关键词：neural tube defects/embryonal carcinoma/osteosarcoma