TGF-? receptor complex is a new addition to the family of human tumor suppressor genes and inactivation of these receptors is important in multiple human malignancies. Because human cancer cells frequently demonstrate resistance to the normal growth inhibitory effects of TGF-?, it has been proposed that the development of such TGF-? resistance represents a significant step during carcinogenesis. We have demonstrated a strong correlation between the resistance to TGF-? and gross structural abnormalities in the TGF-? type II receptor (RII) gene in human gastric cancers. In addition, we have reported that mutation and transcriptional repression of the TGF-? type II receptor correlated with the loss of responsiveness of tumor cell lines to TGF-?. Transcriptional repression of the TGF-? type II receptor (T?RII) gene is one of several mechanisms leading to TGF-? resistance. Our research has suggested that a pharmacologic augmentation of TGF-beta signaling pathways in human cancers such as gastric cancer may be a potential therapeutic strategy. Previously, we showed that MS-275, a synthetic inhibitor of histone deacetylase (HDAC), specifically induces the expression of the T?RII gene and restores the TGF-? signaling in human breast cancer cell lines. In our recent study, we demonstrated that treatment with the HDAC inhibitor induces T?RII promoter activity by the recruitment of PCAF protein to the NF-Y complex interacting with the inverted CCAAT box in the T?RII promoter. It has been shown that infection of cells with human T-cell lymphotropic virus-1 (HTLV-1), hepatitis B virus (HBV), and human papillomavirus (HPV) modulates TGF-? signaling. We, therefore, explored the molecular mechanisms of suppression of TGF-? signaling by viral oncoproteins, such as HBV-pX, HTLV-1-Tax, or HPV-E7. We discovered that the HBV encoded oncoprotein pX amplifies and augments TGF-? signaling through a direct interaction with its signaling intermediate, Smad4. This observation led to a mechanism of disease pathogenesis following HBV infection. The HTLV-I oncoprotein Tax is implicated in the various clinical manifestations associated with infection by HTLV-1 including an aggressive and fatal T-cell malignancy. A previous report demonstrated that HTLV-1-infected T-cell lines became resistant to TGF-? growth inhibitory activity. We found that Tax suppresses TGF-? signaling through direct interaction with Smad proteins, suggesting that the inhibition of TGF-? signaling by Tax may lead to the HTLV-1-associated leukemogenesis. The human papillomavirus (HPV) oncoprotein E7 is implicated in the etiology of cervical cancer associated with infection by HPV. HPV-positive cells develop resistance to TGF-? growth inhibitory activity through the inhibition of hypophosphorylation of pRb by papillomavirus type 16 E7 oncoprotein. We have demonstrated that E7, in addition to its well-known effects on pRb, significantly blocks both Smad transcriptional activity and the ability of TGF-? to inhibit DNA synthesis. E7 interacts constitutively with Smad2, Smad3, and Smad4, and blocks Smad3 binding to its target sequence on DNA. Our results suggest that suppression of Smad-mediated signaling by E7 may contribute to HPV-associated carcinogenesis.
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