Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
STRUCTURE REGULATION AND ONCOGENIC MECHANISMS OF HTLV-1 AND HTLV-2 (MEETING ABSTRACT)
Fifteenth Symposium of the International Association for Comparative Research on Leukemia and Related Disease. October 6-11, 1991, Padova/Venice, Italy, p. 69, 1991.. Unique Identifier : AIDSLINE ICDB/92682414 Pavlakis GN; Feiber BK; Ciminale V; Unge T; Solomin L; Derse D; Copeland N; Jenkins N; Harrison JE; ABL-Basic Res. Program, NCI-FCRDC, Frederick, MD 21702-1201
Abstract:
HTLV and HIV are complex retroviruses producing several additional proteins and regulating their expression via two essential regulatory factors. While HIV-1 produces more than 30 different mRNAs, HTLV-1 had been shown to produce three mRNAs. We investigated whether additional mRNAs can be produced by HTLV-1 by alternative splicing. A full-length molecular clone of HTLV-1, generated from lymphocytes of an ATL patient, was transfected into HeLa cells. Cytoplasmic RNA was isolated, reverse-transcribed and PCR amplified using different pairs of primers. The resulting cDNAs were cloned and sequenced. Interestingly, in addition to the two known 3' splice sites (3'ss) used for the env and tax/rex mRNAs, respectively, four additional 3'ss were identified. Three of these splice sites are in the 'X' region at the 3' part of the genome, and their utilization offers the possibility for the expression of two open-reading frames known to exist within the X-region, ORF1 and ORF2. The use of these splice sites in combination with exon 2 generates mRNAs with the potential to encode two novel hybrid proteins: Rex-ORF1 of 152 amino acids and Tax-ORF2 of 241 amino acids. The expression and function of these proteins in human cells is under investigation. Our data suggest that HTLV-1 produces at least 7 different mRNAs; therefore, expression of HTLV-1 is more complex than previously thought. One of the two essential regulatory proteins of HTLV-1, Tax, is a transcriptional activator of the viral LTR promoter. Tax acts via a cis-acting element of approx 10 bp found in three copies upstream of the TATA box. This element acts as an enhancer of promoter activity in the presence of Tax, and shares homology with the cyclic AMP-responsive element found in many cellular promoters. This core element also exists within the c-fos promoter. We have shown that c-fos promoter is activated by Tax after transfections in mouse cells in tissue culture. The second essential regulatory protein of HTLV-1, Rex, is an RNA-building protein that interacts directly with a cis-acting element in the HTLV-1 LTR named Rex-responsive element (RXRE). Rex is responsible for the transport of the unspliced and singly spliced HTLV-1 mRNAs to the cytoplasm and the production of the structural proteins Gag, Pol and Env, which leads to the generation of virus particles. We have generated transgenic mouse lines producing Tax1 or Tax2 of HTLV-1 and HTLV-2, respectively, using different promoters. Some of the transgenic lines display an abnormal tail phenotype consisting of an acanthotic and parakeratotic epidermis, hyperplasia of the dermis with vascular ectasia and accumulation of pyknotic cells and neutrophils; Tax mRNA was detected in several tissues of these animals, including tail, brain, lung, liver and muscle. Examination of the c-fos expression in the tissues of the transgenic animals revealed high levels of c-fos expression in the tissues, especially the tail and brain. Tax expression vectors producing high levels of Tax resulted in transgenic animals developing multiple Schwann cell tumors with very high frequency early after birth. The results indicate that Tax protein is responsible for promoting tumor development in these transgenic mice. Tax may participate in tumorigenesis via the transcriptional activation of cellular oncogenes such as fos. We have also shown that Tax can activate in trans the expression of an HTLV-1 LTR-CAT construct introduced into mice. By mating the LTR-CAT animals to Tax-producing animals, we were able to demonstrate transactivation in specific tissues depending on the promoter used for tax expression. This system provides an expression switch allowing the controlled expression of genes in some mouse tissues.
Keywords: Animal Cloning, Molecular Gene Amplification Gene Products, pol/GENETICS Gene Products, rex/GENETICS Gene Products, tax/GENETICS Genes, fos/GENETICS Genes, Viral/GENETICS Genome, Viral Hela Cells Human HIV Long Terminal Repeat/GENETICS HTLV-I/*GENETICS HTLV-II/*GENETICS Leukemia, T-Cell/*GENETICS Open Reading Frames/GENETICS Polymerase Chain Reaction Proteins/*GENETICS RNA, Messenger/GENETICS Transfection ABSTRACT 920930
M9290916
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
