HTLV-1 p27rex stabilizes human interleukin-2 receptor alpha chain mRNA.

Abstract

Expression of the pX gene products (p40tax, p27rex and p21X‐III) of human T cell leukemia virus type 1 (HTLV‐1), which is known to be a causative agent of adult T cell lymphoma/leukemia, induces expression of the interleukin‐2 receptor alpha chain (IL‐2R alpha) on infected T cells. Comparison of IL‐2R alpha promoter activities has revealed that the transcriptional activation of the promoter alone cannot explain the large numbers of IL‐2R alpha expressed on HTLV‐1 infected cells. We found that the rates of the IL‐2R alpha mRNA degradation were greatly reduced in pX‐positive cells as compared with pX‐negative cells. Simultaneous transfection of the expression vector plasmid containing IL‐2R alpha cDNA and similar plasmids containing various pX sequences showed that p27rex elongated the half life of IL‐2R alpha mRNA. As p27rex did not affect the transport of the IL‐2R alpha mRNA from nucleus to cytoplasm, prolongation of the IL‐2R alpha mRNA half life by p27rex is ascribed to stabilization of the mRNA. Experiments using deletion mutants and chimeric constructs of the IL‐2R alpha cDNA demonstrated that the coding sequence but not the 5′ or 3′ untranslated region of the IL‐2R alpha mRNA sequence is responsible for its protection by p27rex.

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

“…The pX region of HTLV-I lies near the 3 H region of the env gene and extends into the U3 region of the 3 H LTR. Within the pX region are four overlapping open reading frames encoding six functionally distinct proteins (Kanamori et al, 1990;Koralnik et al, 1993;Wagner and Green, 1993;Kubota et al, 1996;Derse et al, 1997;Lairmore et al, 2000).…”

“…With respect to HIV-1-induced neurologic disease, release of potentially neurotoxic viral gene products into the CNS by HTLV-I-infected cells may be a critical determinant in mediating neuroin¯ammation and bystander damage within the CNS. p27 III (Rex) has been shown to increase the nuclear export and cytoplasmic localization of nonspliced and singly spliced viral RNA and to stabilize interleukin-2 receptor a (IL-2Ra) mRNA (Kanamori et al, 1990) (Fig. 2).…”

Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

“…Rex relieves constraints on the export of viral transcripts conferred by cis-acting negative elements identi®ed in the 5' and 3' LTRs (Black et al, 1991(Black et al, , 1994GroÈ ne et al, 1996;King et al, 1998). In addition, Rex appears to be a direct inhibitor of splicing (Bakker et al, 1996;GroÈ ne et al, 1996) and may therefore contribute to the oncogenic potential of HTLV-1 (Kanamori et al, 1990;McGuire et al, 1993).…”

Enhancement of nucleocytoplasmic export of HTLV‐1 Rex mRNA through cis and trans interactions of the mRNA with the complex of Rex protein and Rex‐responsive element

“…A functional NOS in Rex has been shown to be critical for Rex activitypoint mutations which abrogate the nucleolar localising capacity of the protein also inhibit completely the ability of Rex to promote transport of unspliced forms of viral RNA out of the nucleus [24]. Rex has also been found to stabilise the mRNA of the Tac subunit of the receptor for IL-2 [25], and an intact NOS is required for the activity [26]. Mutation of the NOS can abrogate both RNA binding and nucleolar localisation and it is not clear from these data whether a lack of Rex in the nucleoli is part of the reason for the loss of the functioning of Rex in vivo.…”