Abstract
Binding of high risk human papillomavirus (HPV) E6 protein to E6-associated protein (E6AP), a cellular ubiquitin-protein ligase, enables E6AP to ubiquitinate p53, leading to p53 degradation in cervical cancer cells such as HeLa cells. Here we report that Pitx2a, a bicoid-type homeodomain transcription factor, can bind to HPV E6 protein and inhibit E6/E6AP-mediated p53 degradation. Deletion of the Pitx2a homeodomain abrogates its ability to bind to HPV E6 protein and to induce p53 accumulation in HeLa cells, suggesting that the homeodomain of Pitx2a is essential for inhibition of E6/E6AP-mediated p53 degradation. Recombinant Pitx2a can also block E6/E6AP-mediated p53 degradation in vitro, indicating that this function of Pitx2a is independent of its transcription activity. Pitx2a does not regulate Hdm2-mediated p53 degradation, because Pitx2a does not affect p53 protein levels in HPV-negative cells, such as HCT116, U2OS, and C33A cells. In addition, Pitx2a-induced p53 is transcriptionally active and maintains its specific DNA binding activity in HeLa cells. Taken together, these findings suggest that, by binding to E6, Pitx2a interferes with E6/E6AP-mediated p53 degradation, leading to the accumulation of functional p53 protein in HeLa cells.
Highlights
Pitx2 is a bicoid-type homeodomain transcription factor, which was originally identified as a candidate gene for Rieger syndrome, an autosomal dominant genetic disease characterized by craniofacial dysmorphologies as well as defects in the heart, limb, and pituitary (1)
Pitx2a-induced p53 is transcriptionally active and maintains its specific DNA binding activity. These findings indicate that binding of Pitx2a to human papillomavirus (HPV) type 18 E6 protein interferes with E6/E6-associated protein (E6AP)-mediated p53 degradation, leading to the accumulation of functional p53 protein and the induction of cell cycle arrest in HeLa cells
We have demonstrated in this article that Pitx2a, a homeodomain transcription factor, can bind to high risk HPV type 18 E6 protein and subsequently interfere with E6/E6AP-mediated p53 degradation, leading to p53 accumulation in HeLa cells
Summary
Pitx is a bicoid-type homeodomain transcription factor, which was originally identified as a candidate gene for Rieger syndrome, an autosomal dominant genetic disease characterized by craniofacial dysmorphologies as well as defects in the heart, limb, and pituitary (1). Pitx was identified as a component of the Wnt signaling pathway, controlling cell proliferation in a tissue-specific manner via regulation of its downstream target genes, such as cyclin D1, D2, and Myc (9, 10). HeLa cells, derived from cervical carcinoma, express wild-type p53 but only at a very low level, because p53 is targeted for ubiquitination and degradation by HPV E6 protein. E6/E6AP-mediated p53 degradation was believed to be the major mechanism leading to cervical carcinoma associated with high risk HPVs (11–14). Pitx2a-induced p53 is transcriptionally active and maintains its specific DNA binding activity These findings indicate that binding of Pitx2a to HPV type 18 E6 protein interferes with E6/E6AP-mediated p53 degradation, leading to the accumulation of functional p53 protein and the induction of cell cycle arrest in HeLa cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
