Studies of the immortalizing activity of HTLV type 1 Tax, using an infectious molecular clone and transgenic mice.
Expression of Tax in the mature lymphoid compartment of transgenic mice resulted in a lymphoproliferative malignancy of natural killer cells and cytotoxic T lymphocytes. Transgenic mouse tumors exhibited mutations in the p53 tumor suppressor gene, and functional inactivation of wild-type p53 protein. Tax transgenic mice heterozygous for the p53 gene exhibited more rapid tumor dissemination and accelerated mortality. Studies of Tax trans-activation in an infectious clone of HTLV-1 demonstrated a critical role for nuclear factor B activation in lymphocyte immortalization. A mutant disrupting Tax activation of the cAMP response element binding (CREB) protein resulted in preferential immortalization of CD8(+) lymphocytes, rather than preferential immortalization of CD4(+) lymphocytes seen with the wild-type infectious clone. A mutation disrupting Tax interaction with CREB-binding protein, CBP, did not affect lymphocyte immortalization by the infectious molecular clone. These models provide new insights into the molecular details of HTLV-1 leukemogenesis.
Ratner
L
L
Washington University School of Medicine, St. Louis, Missouri 63110, USA. lratner@imgate.wustl.edu
Portis
T
T
Robek
M
M
Harding
J
J
Grossman
W
W
D000818:Animals; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D016356:Gene Products, tax / Q000235:genetics* / Q000378:metabolism; D016158:Genes, p53; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D016356:Gene Products, tax; D009687:Nuclear Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53