Mutant Tax Protein from Bovine Leukemia Virus with Enhanced Ability To Activate the Expression of c-fos

ABSTRACT Bovine leukemia virus (BLV) is the etiologic agent of enzootic bovine leukosis. We previously identified several mutants of the BLV Tax protein with an ability to transactivate transcription via the BLV enhancer that is significantly greater than that of the wild-type Tax protein. Moreover, the mutant proteins also activated other viral enhancers, such as the enhancer of human T-cell leukemia virus type 1, which cannot be activated by wild-type BLV Tax. In this study, we demonstrated that the mutant proteins but not wild-type protein activate the upstream sequence of the human c-fos gene, which contains two major cis-acting elements, the CArG box and cyclic AMP-responsive element (CRE) motif. The mutant protein also strongly increased levels of endogenous c-fos mRNA in both human and bovine cell lines. On the other hand, the wild-type Tax protein has no activity to activate the expression of human c-fos, indicating that wild-type BLV Tax might discriminate between human and bovine c-fos promoter sequences. Deletion and point-mutational analysis of the cis-acting elements revealed that both the CArG box and the CRE motif were indispensable for the activation of c-fos by the mutant BLV Tax protein. Our results suggest that the mutant BLV Tax proteins might not only have the ability to enhance the production of virus particles but might also have increased ability to induce leukemia.

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The Region between Amino Acids 245 and 265 of the Bovine Leukemia Virus (BLV) Tax Protein Restricts Transactivation Not Only via the BLV Enhancer but Also via Other Retrovirus Enhancers

Journal of Virology ◽

10.1128/jvi.74.23.10939-10949.2000 ◽

2000 ◽

Vol 74 (23) ◽

pp. 10939-10949 ◽

Cited By ~ 28

Author(s):

Shigeru Tajima ◽

Yoko Aida

Keyword(s):

Amino Acids ◽

Bovine Leukemia Virus ◽

Leukemia Virus ◽

Mutant Protein ◽

Target Sequence ◽

Wild Type ◽

Cell Leukemia Virus Type ◽

Mutant Proteins ◽

Tax Protein ◽

Responsive Element

ABSTRACT Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis and is closely related to human T-cell leukemia virus type 1 (HTLV-1). The Tax protein of BLV acts through the 5′ long terminal repeat (LTR) of BLV and activates the transcription of BLV. In this study, we amplified tax genes from BLV-infected cattle using PCR. We cloned the genes and monitored the transcriptional activities of the products. Seven independent mutant Tax proteins, with at least one amino acid substitution between residues 240 and 265, exhibited a markedly stronger ability to stimulate the viral LTR-directed transcription than the wild-type Tax protein. Analysis of chimeric Tax proteins derived from wild-type and mutant Tax proteins clearly demonstrated that a single substitution between residue 240 and 265 might be critical for the higher activities of the Tax mutant proteins. Furthermore, it appeared that transient expression of a Tax mutant protein was better able to increase the production of viral proteins and particles from a defective recombinant proviral clone of BLV than was wild-type Tax. Analysis of mutations within the U3 region of the LTR revealed that a cyclic AMP-responsive element in Tax-responsive element 2 might be sufficient for the enhanced activation mediated by the mutant proteins. In addition to the LTR of BLV, other viral enhancers, such as the enhancers of HTLV-1 and of mouse mammary tumor virus, which cannot be activated by wild-type BLV Tax protein, were activated by a Tax mutant protein. Our observations suggest that the transactivation activity and target sequence specificity of BLV Tax might be limited or negatively regulated by the region of the protein between amino acids 240 and 265.

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Mutational analysis of human T-cell leukemia virus type I Tax: regions necessary for function determined with 47 mutant proteins.

Journal of Virology ◽

10.1128/jvi.66.12.7183-7192.1992 ◽

1992 ◽

Vol 66 (12) ◽

pp. 7183-7192 ◽

Cited By ~ 85

Author(s):

O J Semmes ◽

K T Jeang

Keyword(s):

T Cell ◽

Virus Type ◽

Mutational Analysis ◽

Leukemia Virus ◽

Type I ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Mutant Proteins ◽

Human T Cell ◽

T Cell Leukemia Virus

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Expression status of Tax protein in human T-cell leukemia virus type 1-transformed MT4 cells: recall of MT4 cells distributed by the NIH AIDS Research and Reference Reagent Program.

Journal of Virology ◽

10.1128/jvi.71.9.6277-6278.1997 ◽

1997 ◽

Vol 71 (9) ◽

pp. 6277-6278 ◽

Cited By ~ 14

Author(s):

K T Jeang ◽

D Derse ◽

M Matocha ◽

O Sharma

Keyword(s):

T Cell ◽

Leukemia Virus ◽

Reference Reagent Program ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Tax Protein ◽

Human T Cell ◽

T Cell Leukemia Virus ◽

Expression Status

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Cloning of Novel Isoforms of the Human Gli2 Oncogene and Their Activities To Enhance Tax-Dependent Transcription of the Human T-Cell Leukemia Virus Type 1 Genome

Journal of Virology ◽

10.1128/jvi.72.5.3958-3964.1998 ◽

1998 ◽

Vol 72 (5) ◽

pp. 3958-3964 ◽

Cited By ~ 31

Author(s):

Akira Tanimura ◽

Shingo Dan ◽

Mitsuaki Yoshida

Keyword(s):

T Cell ◽

Cell Lines ◽

Virus Type ◽

Leukemia Virus ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Tax Protein ◽

Human T Cell ◽

T Cell Leukemia Virus

ABSTRACT The expression of human T-cell leukemia virus type 1 (HTLV-1) is activated by interaction of a viral transactivator protein, Tax, and cellular transcription factor, CREB (cyclic AMP response element binding protein), which bind to a 21-bp enhancer in the long terminal repeats (LTR). THP (Tax-helping protein) was previously determined to enhance the transactivation by Tax protein. Here we report novel forms of the human homolog of a member of the Gli oncogene family, Gli2 (also termed Gli2/THP), an extended form of a zinc finger protein, THP, which was described previously. Four possible isoforms (hGli2 α, β, γ, and δ) are formed by combinations of two independent alternative splicings, and all the isoforms could bind to a DNA motif, TRE2S, in the LTR. The longer isoforms, α and β, were abundantly expressed in various cell lines including HTLV-1-infected T-cell lines. Fusion proteins of the hGli2 isoforms with the DNA-binding domain of Gal4 activated transcription when the reporter contained a Gal4-binding site and one copy of the 21-bp sequence, to which CREB binds. This activation was observed only in the presence of Tax. The 21-bp sequence in the reporter was also essential for the activation. These results suggest that simultaneous binding of hGli2 and CREB to the respective sites in the reporter seems to be critical for Tax protein to activate transcription. Consequently, it is probable that the LTR can be regulated by two independent signals through hGli2 and CREB, since the LTR contains the 21-bp and TRE2S sequences in the vicinity.

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