M. Traidej et al., The roles of E6-AP and MDM2 in p53 regulation in human papillomavirus-positive cervical cancer cells, ANTISENSE N, 10(1), 2000, pp. 17-27
The p53 tumor suppressor is regulated by the MDM2 oncoprotein through a neg
ative feedback mechanism. MDM2 promotes the ubiquitination and proteasome-d
ependent degradation of p53, possibly by acting as a ubiquitin ligase, In c
ervical cancer cells containing high-risk human papillomaviruses (HPV), p53
is also targeted for degradation by the HPV E6 oncoprotein in combination
with the cellular E6-AP ubiquitin ligase, In this report, we describe the i
dentification of efficient antisense oligonucleotides against human E6-AP,
The roles of MDM2 and E6-AP in p53 regulation were investigated using a nov
el E6-AP antisense oligonucleotide and a previously characterized MDM2, ant
isense oligonucleotide. In HPV16-positive and HPV-18 positive cervical canc
er cells, inhibition of E6-AP, but not MDM2, expression results in signific
ant induction of p53, In HPV-negative tumor cells, p53 is activated by inhi
bition of MDM2 but not E6-AP, Furthermore, treatment with both E6-AP and MD
M2 antisense oligonucleotides in HPV-positive cells does not lead to furthe
r induction of p53 over inhibition of E6-AP alone. Therefore, E6-AP-mediate
d degradation is dominant over MDM2 in cervical cancer cells but does not h
ave a significant role in HPV-negative cells.