Feline Leukemia Virus Long Terminal Repeat Activates Collagenase IV Gene Expression through AP-1

Abstract

Leukemia and lymphoma induced by feline leukemia viruses (FeLVs) are the commonest forms of illness in domestic cats. These viruses do not contain oncogenes, and the source of their pathogenic activity is not clearly understood. Mechanisms involving proto-oncogene activation subsequent to proviral integration and/or development of recombinant viruses with enhanced replication properties are thought to play an important role in their disease pathogenesis. In addition, the long terminal repeat (LTR) regions of these viruses have been shown to be important determinants for pathogenicity and tissue specificity, by virtue of their ability to interact with various transcription factors. Previously, we have shown that, in the case of Moloney murine leukemia virus, the U3 region of the LTR independently induces transcriptional activation of specific cellular genes through an LTR-generated RNA transcript (S. Y. Choi and D. V. Faller, J. Biol. Chem. 269:19691–19694, 1994; S.-Y. Choi and D. V. Faller, J. Virol. 69:7054–7060, 1995). In this report, we show that the U3 region of exogenous FeLV LTRs can induce transcription from collagenase IV (matrix metalloproteinase 9) and monocyte chemotactic protein 1 (MCP-1) promoters up to 12-fold. We also show that AP-1 DNA-binding activity and transcriptional activity are strongly induced in cells expressing FeLV LTRs and that LTR-specific RNA transcripts are generated in those cells. Activation of mitogen-activated protein kinase kinases 1 and 2 (MEK1 and -2) by the LTR is an intermediate step in the FeLV LTR-mediated induction of AP-1 activity. These findings thus suggest that the LTRs of FeLVs can independently activate transcription of specific cellular genes. This LTR-mediated cellular gene transactivation may play an important role in tumorigenesis or preleukemic states and may be a generalizable activity of leukemia-inducing retroviruses.

Leukemia virus long terminal repeat activates NFκB pathway by a TLR3-dependent mechanism

“…The U3-LTR region sufficient for gene transactivational activity does not contain a readable protein-coding frame. A specific RNA transcript for this region has been consistently detected in cells expressing only the U3-LTR as well as cells infected with the full-length virus (Ghosh and Faller, 1999). We have also demonstrated that LTR from nonpathogenic endogenous FeLV, which cannot transactivate cellular genes, does not make LTR specific transcript (Ghosh, Roy-Burman, and Faller, 2000).…”

“…This finding suggested that the LTR may have some role in the induction of preleukemic hyperplasia in addition to its activity as an enhancer element. Other studies demonstrated that transient or stable expression of the U3-LTR region of Mo-MuLV or feline leukemia virus (FeLV) in fibroblasts of murine or feline origin, as well as in human lymphoid cell lines, induces expression of specific cellular genes, such as collagenase IV, monocyte chemotactic protein 1 (MCP-1), c-jun and MHC class I Ghosh and Faller, 1999;Koka, van de Mark, and Faller, 1991;Wilson, Flyer, and Faller, 1987). Upregulation of these genes occur at the level of transcription and is independent of the physical location of the LTR or the responding cellular genes.…”

“…The mechanism of LTR-mediated transactivation of cellular genes has not been elucidated. We have previously reported that only the U3 region of the LTR is necessary for this transactivational activity and, in case of FeLV, it can be as small as 210 bp (Choi and Faller, 1995;Ghosh and Faller, 1999;Ghosh, Roy-Burman, and Faller, 2000). The U3-LTR region sufficient for gene transactivational activity does not contain a readable protein-coding frame.…”

Identification of LTR‐specific small non‐coding RNA in FeLV infected cells

“…Membranes were hybridized with appropriate 32 P-labelled probe using Express-Hyb hybridization solution (Clontech) according to the manufacturer's protocol. DNA templates used for probe preparation were either the 341 bp U3-LTR insert in the 61E-LTR plasmid for LTR probe [11], or a PCR-amplified product of the envelope region of FeLV 61E using specific primers (FeLV EnvA and FeLV EnvB, Table 1).…”

“…Analysis of the necessary FeLV U3-LTR sequence for gene transactivation revealed that this region does not have any valid protein-coding frame. It was demonstrated previously that leukemogenic viruses such as Mo-MuLV and FeLV generate LTRspecific RNA transcripts [11,17]. Other studies on non-oncogenic endogenous FeLV LTRs demonstrated that they neither make specific transcripts like their exogenous counterpart, nor do they transactivate cellular gene expression [18].…”