Ikbifkb Nfki

Death Substrates l

Apoptosis-*-

Nuclear Localization

HTLV Tai

Figure 12-12. Tax interferes with TNF-induced intracellular signaling events. The TNF receptor can transduce several signaling cascades that result either in apoptosis or cell growth and, therefore, protection from apoptosis. The apoptotic signal is delivered through a caspase cascade (initiated by the activation of caspase 8 through recruitment to the cell membrane and subsequent activation of caspase 3) that results in the cleavage of death substrates, which, upon nuclear localization, initiate apoptotic events. The protective events triggered by receptor recognition are mediated through a kinase cascade that results in the activation of trans-activators of transcription, among them NF-kB and cJun. These trans-activators promote cell growth and serve to activate anti-apoptotic genes. Tax affects these pathways by activating the transcriptional activators NF-kB and cJun by various mechanisms and inhibiting several steps in the caspase cascade. Tax activates IKKs (1) and promotes the dissociation and degradation of IkB (2), and trans-activates the cJun gene (not shown). Tax has also been shown to trans-activate genes that serve as activated caspase 3 inhibitors (3), and presumably trans-activates proteins that could inhibit the caspase cascade at the level of caspase 8 (4), although the exact step that is blocked remains unclear. (Adapted from Screaton and Xu,82 with permission.)

et al.,105 in a population study, indicated that certain MHC class II antigens confer susceptibility to the development of either ATL or HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). They showed that 42 percent of HTLV-1 positive individuals expressed the HLA-DR15 allele, as opposed to 4.8 percent of HTLV-1 negative individuals. In addition, 78 percent of positive individuals expressed the HLA-DQ1 allele, as opposed to 53 percent of negative individuals. There were no alleles expressed by negative individuals in greater frequency than positive individuals that proved to be statistically significant, indicating that there are no alleles among these two loci that would confer absolute resistance to HTLV-1 infection.

The investigators did not find any significant difference between the HLA make-up of ATL patients and asymptomatic carriers with regards to type 2 loci. They did, however, find a significant difference in allelic frequencies between the previous two groups and patients who developed HAM/TSP. There were two DRB1 alleles with higher frequency among the asympto-

Plasma Membrane Effector Cell

FasL(CD95L)

Death Substrates

Procaspas e 3 (Inactive)

Trans -Suppresses

Death Substrates

Nuclear Localization

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