Studies Utilising a Transgenic Mouse Model to Investigate the Pathogenesis of HTLV-I Tax

Hall, A. Peter (1999) Studies Utilising a Transgenic Mouse Model to Investigate the Pathogenesis of HTLV-I Tax. PhD thesis, University of Glasgow.

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In order to investigate the contribution that the HTLV-I (Human T-cell Leukaemia Virus Type I) tax oncogene contributes to the transformed phenotype we generated transgenic mice that expressed the HTLV-I tax transgene under the regulatory influence of the CD3- s promoter-enhancer elements. These mice developed a variety of different types of pathology, the most pertinent of which were tumours (overall incidence 28/57 (49%)). The principal tumours were mesenchymal tumours which developed at sites of wounding (ear and tail tips) (overall incidence 18/31 (58%); average latency 202.5 days), and salivary and mammary adenomas (overall incidence 10/26 (38%); average latency 399 days). Immunocytochemical analysis of these tumours revealed that subpopulations of tumour cells expressed high levels of Tax protein as well as Myc, Fos, Jun and p53 proteins. Analysis of these tumours using the TUNEL (Terminal dUTP Nick End Labelling) technique revealed a similar pattern of apoptosis. Dual immunofluorescent localisation of Tax expressing cells with cells undergoing apoptosis revealed a remarkable degree of coincidence between these processes indicating that Tax expression and apoptosis are intimately linked in vivo. When CD3-tax transgenic mice were bred onto a p53 null or hemizygous background the resultant tumours which emerged at ear and tail tips were identical to the original cohort of tumours indicating a lack of cooperation between tax and p53 (average latency for mesenchymal tumours emerging on a p53 wild type background: 277d (9.2months) and 128d (4.3 months) cf p53+/- background; 233d (7.8 months) and 156d (5.2 months)). A Tax expression system was also developed in vitro using a pBabe retroviral vector which transcribed a Tax-MER (Tax-modified oestrogen receptor) fusion product. This fusion protein was dependent upon functional activity by induction with 4-hydroxy tamoxifen. The results of these experiments using a CREB/ATF responsive reporter gene indicated that this system produced a functional fusion protein that was well regulated by 4-hydroxy tamoxifen. Functional mutants of Tax were made (Ml, M47 and C23S) based on published data (Smith and Greene, 1990; Semmes and Jeang, 1992) which were designed to segregate the functional domains of Tax. Analysis of these mutants indicated that M47 least efficiently induced apoptosis in vitro. In our hands this protein also least efficiently transactivated the CREB/ATF pathway (although transactivation of the NFkB pathway was difficult to determine in this assay system). These results may indicate the general importance of the CREB/ATF pathway for apoptotic induction. Similarly these results, together with the transgenic mouse experiments, may also indicate that low levels of Tax expression does not induce apoptosis.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Virology, Genetics
Date of Award: 1999
Depositing User: Enlighten Team
Unique ID: glathesis:1999-76207
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 16:28
Last Modified: 19 Nov 2019 16:28

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