Recapitulation of the effects of the human papillomavirus type 16 E7 oncogene on mouse epithelium by somatic Rb deletion and detection of pRb-independent effects of E7 in vivo
Recapitulation of the effects of the human papillomavirus type 16 E7 oncogene on mouse epithelium by somatic Rb deletion and detection of pRb-independent effects of E7 in vivo
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DOI：
10.1128/mcb.23.24.9094-9103.2003
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发表时间：
2003-12-01
影响因子：
5.3
通讯作者：
Lambert, PF
中科院分区：
文献类型：
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作者：
Balsitis, SJ;Sage, J;Lambert, PF
虽然人类乳头瘤病毒(HPV)E7癌基因与人类宫颈癌的发生有关，但其致癌机制尚不清楚。E7最早被发现和最被认识的功能是它与视网膜母细胞瘤肿瘤抑制因子(PRB)的结合和失活，但至少还有18种其他生物活性也被报道。因此，目前还不清楚这许多活动中的哪一种对E7的致癌潜力有贡献。我们使用Cre-lox系统来消除转基因小鼠表皮中pRb的表达，并将结果与早期相同组织中E7表达的影响进行了比较。表皮中缺乏pRb的小鼠表现为上皮细胞增殖、DNA合成异常和分化不良。此外，Rb缺失的表皮(即由缺失Rb的细胞组成的表皮)表现出中心体异常，未能阻止细胞周期对电离辐射的响应。在皮肤中表达E7的转基因小鼠表现出相同的表型范围。总之，在幼年小鼠的RB缺失的表皮和表达E7的表皮之间几乎没有发现差异。然而，当E7和Rb在同一组织中同时表达和缺失时，可以观察到更多的增生和不典型增生。这些发现表明，Rb途径的失活在很大程度上可以解释E7‘S早期的表型，但E7的pRb非依赖于pRb的活性在体内是可以检测到的。
Although the human papillomavirus (HPV) E7 oncogene is known to contribute to the development of human cervical cancer, the mechanisms of its carcinogenesis are poorly understood. The first identified and most recognized function of E7 is its binding to and inactivation of the retinoblastoma tumor suppressor (pRb), but at least 18 other biological activities have also been reported for E7. Thus, it remains unclear which of these many activities contribute to the oncogenic potential of E7. We used a Cre-lox system to abolish pRb expression in the epidermis of transgenic mice and compared the outcome with the effects of E7 expression in the same tissue at early ages. Mice lacking pRb in epidermis showed epithelial hyperplasia, aberrant DNA synthesis, and improper differentiation. In addition, Rb-deleted epidermis (i.e., epidermis composed of cells with Rb deleted) exhibited centrosomal abnormalities and failed to arrest the cell cycle in response to ionizing radiation. Transgenic mice expressing E7 in skin display the same range of phenotypes. In sum, few differences were detected between Rb-deleted epidermis and E7-expressing epidermis in young mice. However, when both E7 was expressed and Rb was deleted in the same tissue, increased hyperplasia and dysplasia were observed. These findings indicate that inactivation of the Rb pathway can largely account for E7's phenotypes at an early age, but that pRb-independent activities of E7 are detectable in vivo.