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. 1998 Mar 3;95(5):2290-5.
doi: 10.1073/pnas.95.5.2290.

Human papillomavirus type 16 E6 and E7 oncogenes abrogate radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways

S Song  1 , G A Gulliver, P F Lambert
Affiliations

Human papillomavirus type 16 E6 and E7 oncogenes abrogate radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways

S Song et al. Proc Natl Acad Sci U S A. .

Abstract

E6 and E7 oncoproteins from high risk human papillomaviruses (HPVs) transform cells in tissue culture and induce tumors in vivo. Both E6, which inhibits p53 functions, and E7, which inhibits pRb, can also abrogate growth arrest induced by DNA-damaging agents in cultured cells. In this study, we have used transgenic mice that express HPV-16 E6 or E7 in the epidermis to determine how these two proteins modulate DNA damage responses in vivo. Our results demonstrate that both E6 and E7 abrogate the inhibition of DNA synthesis in the epidermis after treatment with ionizing radiation. Increases in the levels of p53 and p21 proteins after irradiation were suppressed by E6 but not by E7. Through the study of p53-null mice, we found that radiation-induced growth arrest in the epidermis is mediated through both p53-dependent and p53-independent pathways. The abrogation of radiation responses in both E6 and E7 transgenic mice was more complete than was seen in the p53-null epidermis. We conclude that E6 and E7 each have the capacity to modulate p53-dependent as well as p53-independent cellular responses to radiation. Additionally, we found that the conserved region (CR) 1 and CR2 domains in E7 protein, which are involved in the inactivation of pRb function and required for E7's transforming function, were also required for E7 to modulate DNA damage responses in vivo. Thus pRb and/or pRb-like proteins likely mediate both p53-dependent and p53-independent responses to radiation.

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Figures

Figure 1
Figure 1
Comparison of levels of DNA synthesis in nontransgenic, E6-transgenic, p53-null, and E7 transgenic epidermis after treatment with radiation. Shown are high-power magnification (×400) images of cross sections of skin from nontransgenic, K14HPV16E6 transgenic, p53−/−, K14HPV16E7, K14HPVE7ΔPTHLE, and K14HPV16E7ΔDLYC transgenic mice stained immunohistochemically for BrdUrd. Mice were either not treated (a, c, e, g, i, and k) or treated with 5 Gy of ionizing radiation 24 hr prior to sacrifice (b, d, f, h, j, and l). Arrows indicate examples of BrdUrd-positive (brown-stained nuclei) cells in the epidermis.
Figure 2
Figure 2
Time course of changes of BrdUrd-positive cells in the epidermis of nontransgenic and E6- and E7-transgenic epidermis treatment with radiation (5 Gy). Graphed are the average percentage of epidermal cells positively stained for BrdUrd at different times after treatment. Error bars indicate standard deviation (SD) among samples from three different mice.
Figure 3
Figure 3
Comparison of decreases in the number of BrdUrd-positive cells in the epidermis of nontransgenic, E6-transgenic, p53-null, E7- and mutant E7-transgenic (E7ΔPTLHE and E7ΔDLYC) epidermis at 24 hr after irradiation. Graphed are the mean percentage of epidermal cells positively stained for BrdUrd.
Figure 4
Figure 4
Levels of p53 in the skin of nontransgenic, E6- and E7-transgenic, and p53-null mice after treatment with radiation. Shown are high power magnifications (×400) of cross sections of skin from nontransgenic, K14HPV16E6 transgenic, and K14HPV16E7 transgenic mice stained immunohistochemically for p53. Mice were either not treated (a, c, e, and g) or treated with 5 Gy of ionizing radiation 24 hr prior to sacrifice (b, d, f, and h). Examples of p53-positive cells are indicated by arrows.
Figure 5
Figure 5
Quantification of p53-positive cells in the epidermis of nontransgenic (♦), E6-transgenic (▪), E7-transgenic (▴), and p53-null (×) epidermis after treatment with radiation. Graphed are the mean percentage of epidermal cells positively stained for p53 at different times after treatment of mice with 5 Gy of radiation. Error bars indicate SD among samples from different mice.
Figure 6
Figure 6
Levels of p21 protein in the epidermal cells of nontransgenic, E6- and E7-transgenic, and p53-null mice after radiation. Shown are high power magnifications (×400) of cross sections of skin from nontransgenic, K14HPV16E6, and K14HPV16E7 transgenic mice that were stained immunohistochemically for p21. Mice were either not treated (a, b, c, and g) or were treated with 5 Gy of ionizing radiation 24 hr prior to sacrifice (d, e, f, and h). Examples of p21-positive cells are indicated by arrows.
Figure 7
Figure 7
Quantification of p21-positive cells in the epidermis of nontransgenic (♦), E6-transgenic (▪), E7-transgenic (▴), and p53-null (×) epidermis after treatment with radiation. Graphed are the percentage of epidermal cells positively stained for p21 at different times after treatment of mice with 5 Gy of radiation.
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