Tax Manipulation of the Jakstat Pathway of Clonal Expansion

Extracellular binding of a variety of the type 1 and type 2 cytokines by cell surface cytokine receptors results in receptor oligomerization and activation of the intracellular JAK/STAT pathway.56 The JAK/STAT pathway is an intracellular signaling cascade that results in the translocation of activated transcription factors to the nucleus where they can recognize response elements associated with the stimulating cytokine. IL-2 response genes are associated with cell cycle progression and proliferation.

HTLV Tax has the ability to activate NF-kB, NF-AT, and AP-

1 (by mechanisms previously discussed), which act together to trans-activate genes for IL-2 and the IL-2 receptor-alpha chain, among others. This results in high surface expression of the IL-

2 receptor and, presumably, a high extracellular concentration of IL-2, which can act as an autocrine factor.57-59 Tax has also been shown to induce the expression of STAT 1 and STAT 5, which would provide a high concentration of intracellular mediators of the IL-2 response signaling cascade.60 In HTLV-infected T cells, this pathway would be hyperactive, and would stimulate the cell to proceed through the cell cycle and proliferate in the absence of either direct or indirect antigenic stimulation. The effects of Tax on the JAK/STAT pathway in T cells are summarized in Figure 12-9.

There is some debate over whether or not this autocrine mechanism is necessary for the development of ATL.61 There have been studies that have shown that some HTLV transformed cells are IL-2 independent.43,62-64 Although the autocrine mechanism may not be required for chronic leuke-mogenesis, it is considered to be an important mechanism for initiating the production of leukemic clones and initial lymphocyte transformation. But it must be acknowledged that some mature ATL cell lines produce little IL-2, so the traditional, ligand-mediated, autocrine mechanism of T cell growth is unlikely to stimulate further clonal expansion in these cells. However, we cannot rule out the dysregulation of the JAK/STAT pathway due to mutations in associated proteins in cells of this stage. Quite possibly, the progression of ATL cells through many rounds of division would confer such mutations that would constitutively activate the JAK/STAT pathway in the absence of IL-2. Such abnormalities would most likely be in the genes for JAK 1/3 or STAT 3/5, or the IL-2R-beta chain. If a mutation were to occur that would render any of these gene products unable to be dephosphorylated after the specific tyrosine residues had been phosphorylated, that would constitutively activate this pathway, and incessantly drive the cell through the cell cycle.

IL-2 independent ATL cells expressed constitutive basal phosphorylation of JAK 3 and, usually, STAT 3 and STAT 5, but IL-2 dependent ATL cells do not.65 IL-2 dependent ATL cells only expressed phosphorylation of JAK 3 and STAT 5 upon addition of IL-2. This observation points to the dependence on accessory mutations in specific protooncogenes in the development of some, but not all, cases of ATL, and explains the discrepancy between IL-2 dependent and IL-2 independent ATL cells.

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