Tax Inhibition of RbMediated Tumor Suppression

The retinoblastoma (Rb) protein plays an important role in the regulation of the cell cycle.66 Rb sequesters the transcription factor E2F-1 in the cytoplasm by physically associating with it and masking its nuclear localization sequence (NLS). In the event of cell division, the cyclin-dependent kinase CDK4 phos-phorylates Rb, causing it to undergo a conformational change that prevents it from binding to E2F-1. At this point E2F-1 is capable of migrating to the nucleus and activating transcription. During interphase, high concentrations of the cyclin-dependent kinase inhibitor p16ink4a (and other members of the same family) prevent the phosphorylation of Rb and promote cell cycle arrest by inhibiting the activity of CDK4.67

HTLV Tax can physically associate with p16ink4a and prevent it from inhibiting CDK4.68,69 In the presence of Tax there is no mechanism to prevent the phosphorylation of Rb. This results in constitutive activation of E2F-1, and the breakdown of tumor suppression. The effects of Tax on Rb are summarized in Figure 12-10.

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