Posttranscriptional regulation of gene expression in retroviruses and human papillomaviruses
Author: Tan, Wei
Date: 1996-05-23
Location: Bakteriologens
Time: 10.00
Abstract
Human immunodeficiency virus type I (HIV-1) is the prototype of complex
retroviruses, whereas human papillomaviruses (HPVs) are nonenveloped,
cricular double- stranded DNA viruses. The HIV- 1 Rev protein is a
posttranscriptional regulator, which acts on its target RNA sequence
termed the Rev-responsive element (RRE) to facilitate nuclear export of
unspliced and partially spliced HIV-1 mRNAs, and to improve their
stability and translatability. Although HPVs are distinct from HIV-l,
gene expression of HPVs may also be posttranscriptionally regulated since
replication of HPV and HIV can be divided into an early regulatory phase
and a late, structural phase. Interaction of Rev and RRE provides a
useful test system to study posttranscriptional regulation of gene
expression in complex retroviruses as well as in DNA viruses, such as
HPVs.
Using the HIV-l tat mRNAs, we demonstrate that the strength of the tat
AUG and the length of the tat ORF are the major factors that
substantially affect translation efficiency of the downstream rev ORF,
whereas intercistronic distance influence reinitiation of the rev ORF to
a lower extent. The presence of the tat ORF strongly inhibited
translation of the downstream rev ORF. This may reflect the requirement
for high levels of Tat at an early stage of the virus life cycle, and may
avoid a premature switch from early to late phase of gene expression to
prevent inefficient virus production.
Unlike HIV-1, we did not find inhibitory RNA sequences in the gag coding
region of equine infectious anemia virus (EIAV). However, sequences
upstream of the gag translational start codon strongly inhibited Gag
production in the absence of Rev and rendered Gag production Rev
dependent. The inhibitory effect could be overcome by Rev and RRE or the
constitutive transport element (CTE) of simian retrovirus type I (SRV-I).
The minimal inhibitory sequence coincides with the EIAV major 5' splice
site. Our results demonstrated that both integrity and location of the
EIAV 5' splice site are required for strong inhibition of EIAV Gag
production
Late gene expression of HPVs is tightly linked to the stage of
differentiation of epithelial cells. We found that the HPV-16 L1 coding
region contains intragenic RNA inhibitory sequences, which repressed L1
production at the posttranscriptional level. Production of the HPV-16 Ll
protein could be activated by Rev and RRE or SRV-l CTE. A major
inhibitory element was localized between nucleotides 5813 and 6150. The
presence of inhibitory sequences on the HPV-16 late mRNAs may explain the
lack of L1 production in nondifferentiated epithelial cells.
The HPV-1 late 3' untranslated region (UTR) also contains inhibitory
sequences, which act posttranscriptionally to inhibit gene expression in
an orientation-dependent manner. The inhibition is caused, at least in
part, by reducing mRNA levels and by inefficient utilization of mRNAs.
The inhibition was counteracted by HIV-l Rev and RRE or SRV-l CTE, or
could be bypassed by transcription in the cytoplasm using a vaccinia
virus-T7 RNA polymerase-based expression system. The major inhibitory
element was localized to an AU-rich sequence between nucleotides 6943 and
7014 near the 5' end of the HPV-l late 3' UTR. We proposed that cellular
factors may bind to the HPV-l inhibitory RNA sequence, resulting in
inhibition of HPV-1 late gene expression.
Using RNA band shift and UV cross-linking assays, we identified two
nuclear proteins (approximately 38- and 52-kDa) and two cytoplasmic
proteins (approximately 50- and 74-kDa) that bind specifically to AU-rich
inhibitory sequences. Deletion of the AU- or U-rich sequences in the
HPV-1 late 3' UTR substantially reduced inhibitory activity, indicating
that the cellular proteins we identified may be involved in inhibition of
HPV- 1 late gene expression in nondifferentiated epithelial cells.
Issue date: 1996-05-02
Publication year: 1996
ISBN: 91-628-2059-1
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