Influence of the human endogenous retrovirus-like element HERV-E.PTN on the expression of growth factor pleiotrophin: a critical role of a retroviral Sp1-binding site

Abstract

Germ line insertion of a human endogenous retroviruslike element (HERV-E.PTN) into the growth factor pleiotrophin (PTN) gene generated a phylogenetically new promoter driving the expression of functional HERV-PTN fusion transcripts. Here we show by in situ hybridization, that HERV-PTN fusion transcripts are expressed in malignant trophoblasts (i.e. choriocarcinoma) and in the proliferative and in the invasive trophoblasts of gestational trophoblastic tissue. Additionally, a 1.9 kb fragment of the HERV-derived PTN promoter was analysed which has strong activity when transiently transfected into choriocarcinoma JEG-3 cells in contrast to HeLa cells. Deletion of the retrovirallyderived promoter portion abolished its activity and an enhancer (+443 to +486) was identi®ed in this region. Electrophoretic mobility shift and supershift experiments identi®ed a Sp1 binding site in this enhancer and site speci®c mutation of this site abolished its activity in choriocarcinoma cells. Sp1 overexpression in Drosophila SL2 cells showed that the enhancer activity is mediated via Sp1 binding in vivo. Furthermore, mutation of the Sp1 binding site reduced the activity of a promoter test fragment in choriocarcinoma cells by 80%. Our result shows that a retroviral Sp1 binding site in the PTN promoter is important for the expression of growth factor pleiotrophin in human choriocarcinoma cells.

An endogenous retroviral long terminal repeat is the dominant promoter for human β1,3-galactosyltransferase 5 in the colon

“…A putative binding site for the placental transcription factor Hand1͞E47 was identified in the EDNRB LTR promoter and was shown to be important for placenta-specific promoter activity, but interaction of Hand1͞ E47 with this site could not be confirmed (11). In other studies, only ubiquitous transcription factors have been confirmed to bind LTR gene promoters (10,12). Therefore, the transcription factors that mediate tissue-specific gene expression from LTR promoters remain largely unknown.…”

The cell survival pathways of the primordial RNA-DNA complex remain conserved in the extant genomes and may function as proto-oncogenes

“…Ancient retroviral inserts express Sp1-binding sites (species-specifi c gene expression stimulatory proteins binding to GC box GGGCGGG motifs). In the drosophila genome, proto-oncogene expressions are intensifi ed by Sp1-stimulated retroviral inserts [90][91][92]. In general, ancient retroviral inserts are activators of protooncogenes [1,93].…”

An alternative approach to medical genetics based on modern evolutionary biology. Part 4: HERVs in cancer

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