P53BS p53 response genes

Figure 12—11. Tax-mediated trans-suppression of p53 response genes. In order to mediate its trans-activating properties, Tax must associate with the cyclic AMP response element binding protein (CREB)-binding protein (CBP) (1). This interaction is required for Tax to augment the binding of CREB to the Tax response element (TRE) in U3 of the proviral LTR, which trans-activates viral RNA transcription. CBP also co-activates the tumor suppressor p53 mediated activation (via its binding site) of genes such as Fas (a cell surface receptor that can transduce apoptotic signals [vide infra]), Bax (a cytoplasmic protein responsible for the induction of specific apoptotic events [vide infra]), and p21 (a cyclin-dependent kinase inhibitor). Tax acts as a competitive inhibitor of the p53/CBP binding event (2) by binding to the same protein-folding domain as p53. The presence of Tax trans-suppresses p53 response genes, and protects the cell from both cell cycle arrest and p53-induced apoptosis.

configurations so that they can interact with promoter elements to initiate transcription.

ADF also exhibits cytoprotective effects. Although the precise mechanisms are unknown, hyperexpression of ADF has shown protective effects against TNFR-mediated apoptosis and Fas-mediated apoptosis.102'103 ADF has also been shown to be a potent co-stimulator of cytokine expression, most notably the expression of IL-2 in Molt-4 cells.104

HTLV-1 infection can apparently disrupt the normal cellular redox status such that the intracellular environment becomes more reducing. This has multiple effects that could result or aid in carcinogenesis. ADF is required to reduce transcription factors so that they can bind to promoter elements. This activity would explain the stimulation of cytokine production in ADF expressing cells, especially the expression of IL-2 in Molt-4 cells (a CD4+ T-cell line) since IL-2 expression can be initiated by both AP-1

and NF-kB. ADF alone could conceivably act as an activator of growth due to these capabilities, causing manipulation of cellular signaling pathways and mechanisms of growth already discussed.

The cytoprotective effects of ADF could also prove to be important in carcinogenesis by providing an alternate mechanism of avoiding immune surveillance or assisting an already existing one mediated by Tax. In any event, ADF alone seems to be able to protect cells against mechanisms of cytotoxicity.

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