the human papillomavirus e6 oncogene represses a cell adhesion pathway and disrupts focal adhesion through degradation of tap63β upon transformation人类乳头瘤病毒e6癌基因压制通过降解细胞粘附通路和扰乱了粘着斑的tap63β转换.pdfVIP

The Human Papillomavirus E6 Oncogene Represses a Cell Adhesion Pathway and Disrupts Focal Adhesion through Degradation of TAp63b upon Transformation ´ Youcef Ben Khalifa, Sebastien Teissier, Meng-Kwang Marcus Tan, Quang Tien Phan, Mathieu Daynac, Wei Qi Wong, Franc¸oise Thierry* Institute of Medical Biology, A*STAR, Singapore Abstract Cervical carcinomas result from cellular transformation by the human papillomavirus (HPV) E6 and E7 oncogenes which are constitutively expressed in cancer cells. The E6 oncogene degrades p53 thereby modulating a large set of p53 target genes as shown previously in the cervical carcinoma cell line HeLa. Here we show that the TAp63b isoform of the p63 transcription factor is also a target of E6. The p63 gene plays an essential role in skin homeostasis and is expressed as at least six isoforms. One of these isoforms, DNp63a, has been found overexpressed in squamous cell carcinomas and is shown here to be constitutively expressed in Caski cells associated with HPV16. We therefore explored the role of p63 in these cells by performing microarray analyses after repression of endogenous E6/E7 expression. Upon repression of the oncogenes, a large set of p53 target genes was found activated together with many p63 target genes related to cell adhesion. However, through siRNA silencing and ectopic expression of various p63 isoforms we demonstrated that TAp63b is involved in activation of this cell adhesion pathway instead of the constitutively expressed DNp63a and b. Furthermore, we showed in cotransfection experiments, combined with E6AP siRNA silencing, that E6 induces an accelerated degradation of TAp63b although not through the E6AP ubiquitin ligase used for degradation of p53. Repression of E6 transcription also induces stabilization of endogenous TAp63b