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Human Papillomavirus Type 16 E6 and E7 Proteins Inhibit Differentiation-dependent Expression of Transforming Growth Factor-ß2 in Cervical Keratinocytes

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute [M. N., J. M. G., C. D. W.], Center for Information Technology [P. M., V. P.], NIH, Bethesda, Maryland, 20892, and Department of Dermatology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111 [Y. L., E. A.]

Infection with high-risk human papillomaviruses (HPVs) represents a major risk factor for the development of cervical cancer. The HPV-16 E6 and E7 proteins are highly expressed in differentiating keratinocytes, where they inactivate the p53 and retinoblastoma (pRb) proteins, two important transcriptional regulators. We have used cDNA expression arrays to identify global alterations in gene expression induced by E6 and E7 in differentiating cultures of human cervical keratinocytes. We show that E6 and E7 decrease expression of TGF-ß2 mRNA and alter expression of multiple TGF-ß-responsive genes involved in cell cycle regulation, apoptosis, and tissue remodeling. E6 and E7 inhibited expression of TGF-ß2 RNA 7-fold (relative effectiveness, E6/E7 > E6 > E7 > control) and decreased secretion of biologically active TGF-ß2 by 70–80% (reduced from 70 to 10 pg/10⁶cells/24 h). Down-regulation occurred through p53- and pRb-dependent pathways. In contrast, E6 and E7 did not alter expression of TGF-ß1 and TGF-ß3. Down-regulation of TGF-ß2 was biologically relevant because the addition of recombinant cytokine (10–200 pg/ml) to E6/E7-expressing cells restored expression of TGF-ß-responsive genes, inhibited growth of keratinocytes, and decreased immortalization by E6 and E7. These results suggest that TGF-ß2- and TGF-ß-responsive genes are important targets for the HPV-16 E6 and E7 oncoproteins in differentiating cervical keratinocytes.

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