EFFECT OF HTLV-I TAT EXPRESSION

Human T-cell leukemia virus type-l (HTLV-I) is a human exogenous
retrovirus linked to adult T-cell leukemia and lymphoma(ATL). In
addition to structural genes, the HTLV-I genome contains regions
encoding a protein termed tat (also px, p40 or Tax) capable of
activating transcription from the viral promoter in the long
terminal repeat (LTR). Considerable research is now being focused
on the mechanisms through which viral transactivating factors
result in neoplastic transformation. Recently, a transgenic mouse
model was developed to study HTLV-I related disease. Tumors
developed in all mice expressing the tat protein; however, the
tumors were not of lymphoid origin. This proposal seeks to study
at the molecular level whether TAT induced neoplasia is specific
for one tissue type or may be manipulated through selective tissue
specific enhancers to develop tumors of lymphoid origin. For this
purpose the interleukin 2 enhancer and the major histocompatability
complex class I enhancer will be used in separate constructions
with the HTLV-l TAT gene. Additional studies will focus on the
pathways which lead to pathology observed in other tissue types
such as the proliferation of ductal cells in the salivary gland of
HTLV-I TAT transgenic mice. Preliminary data suggests that several
growth factors may be stimulated by the elevated levels of Tat
protein expressed in affected tissues. The mechanisms for
increasing tat expression through TAT gene copy number as compared
to integrated TAT transgene structure will be explored
through immunoblot analysis of proteins and restriction enzyme
mapping of the transgenic animal DNA.