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Inhibition of Topoisomerase II Expression by Transforming Growth Factor-ß1 Is Abrogated by the Papillomavirus E7 Protein¹

Departments of Pediatrics [D. J. S.] and Oncological Sciences [R. L. W., N. M., K. L. N.], University of Utah School of Medicine, Salt Lake City, Utah 84132

Transforming growth factor-ß (TGF-ß) protects normal cells from etoposide-induced cell death, yet the mechanism has remained speculative. Studies have shown that etoposide modifies the activity of the topoisomerase II (topo II) enzyme, thereby causing DNA damage and inducing cell death. Expression of topo II is necessary for etoposide-induced cell death, and peak expression of topo II normally occurs during the G₂ phase of the cell cycle. We predicted that by arresting growth in the G₁ phase, TGF-ß1 would prevent the induction of topo II expression that normally occurs subsequent to the G₁-S transition, thereby protecting cells from etoposide-induced cell death. Accordingly, we hypothesized that the inhibition of topo II expression by TGF-ß1 would be dependent on the ability of TGF-ß1 to arrest cell cycle progression in G₁. Using mink lung epithelial cells (Mv1Lu), we found that TGF-ß1 decreases topo II mRNA expression, and the decrease occurs as cells begin to accumulate in the G₁ phase of the cell cycle. Topo II protein expression decreases subsequent to the fall in mRNA expression. In contrast, topo II expression is not affected by TGF-ß1 in cells that fail to undergo G₁ arrest because of inactivation of the retinoblastoma tumor suppressor protein (pRb) by the papillomavirus type 16 E7 protein. Our studies suggest that inhibition of topo II by TGF-ß1 is the principal mechanism that protects mink lung epithelial cells (Mv1Lu) from etoposide-induced toxicity. Furthermore, the inhibition of topo II protein expression by TGF-ß1 is dependent on pRb-mediated cell cycle arrest, suggesting that TGF-ß1 will not reduce the sensitivity of pRb-deficient cancers to etoposide.

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				D. K. Lee, B.-C. Kim, I. Y. Kim, E.-a. Cho, D. J. Satterwhite, and S.-J. Kim The Human Papilloma Virus E7 Oncoprotein Inhibits Transforming Growth Factor-beta Signaling by Blocking Binding of the Smad Complex to Its Target Sequence J. Biol. Chem., October 4, 2002; 277(41): 38557 - 38564. [Abstract] [Full Text] [PDF]