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Abstract
Expression of the platelet-derived growth factor alpha-receptor (PDGFalphaR) gene is tightly controlled in mammalian embryogenesis. A well established model system to study human embryogenesis is the embryonal carcinoma cell line Tera2. We have shown previously that retinoic acid-differentiated Tera2 cells express two PDGFalphaR transcripts of 6.4 kilobase pairs (kb) (encoding the full-length receptor) and 3.0 kb, respectively, whereas in contrast, undifferentiated Tera2 cells express PDFGalphaR transcripts of 1.5 kb and 5.0 kb. Here we show that this switch in PDGFalphaR expression pattern during differentiation of Tera2 cells results from alternative promoter use. In undifferentiated cells, a second promoter is used, which is located in intron 12 of the PDGFalphaR gene. Functional analysis shows that this promoter contains a consensus octamer motif, which can be bound by the POU domain transcription factor Oct-4. Oct-4 is expressed in undifferentiated Tera2 cells but not in retinoic acid-induced differentiated cells. Mutation of the octamer motif decreases promoter activity, while ectopic expression of Oct-4 in differentiated Tera2 cells specifically enhances the activity of this PDGFalphaR promoter. Therefore, we suggest that an important aspect in the maintenance of the undifferentiated state of human embryonal carcinoma cells results from Oct-4 expression, which thereupon activates this PDGFalphaR promoter.
Highlights
Lacks part of the Platelet-derived growth factor (PDGF)␣R gene [5, 6] and displays severe developmental defects in mesodermal and neuroectodermal tissues, often resulting in prenatal lethality [7, 8]
Studies on surgically removed testicular germ cell tumors have shown that the 1.5-kb PDGF ␣-receptor (PDGF␣R) transcript can be used as a selective marker for carcinoma-in situ, seminoma, Platelet-derived growth factor (PDGF)1 and its receptors play a prominent role during early mammalian development
We have examined the regulation of the human PDGF␣R P2 promoter, which gives rise to two transcripts in Tera2 embryonal carcinoma (EC) cells, in order to assess its role in human development and differentiation
Summary
Lacks part of the PDGF␣R gene [5, 6] and displays severe developmental defects in mesodermal and neuroectodermal tissues, often resulting in prenatal lethality [7, 8]. An important model system for studying human early embryogenesis is that of testicular germ cell tumors. We have recently shown that differentiation of Tera EC cells by retinoic acid (RA) is accompanied by a shift in expression of PDGF␣R mRNA variants [11].2. We suggest that an important as- species of 1.5 and 5.0 kb, respectively, are expressed in early pect in the maintenance of the undifferentiated state of human embryonal carcinoma cells results from Oct-4 expression, which thereupon activates this PDGF␣R promoter. Studies on surgically removed testicular germ cell tumors have shown that the 1.5-kb PDGF␣R transcript can be used as a selective marker for carcinoma-in situ, seminoma, Platelet-derived growth factor (PDGF) and its receptors play a prominent role during early mammalian development. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) X95095
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