The E6 proteins of specific cancer-associated human papillomaviruses (
HPVs) complex with and mediate degradation of the cellular anti-oncoge
ne p53 in vitro. A critical property of p53 is its ability to stimulat
e transcription from promoters containing its recognition sequence. HP
V E6, mutant p53 proteins, and several DNA tumor virus oncogenes inhib
it the transcriptional activity of wild-type p53. In this report, the
structural requirements for the interaction between HPV 16 E6 and p53
were examined both in vivo and in vitro. p53-stimulated transcription
was efficiently inhibited by wild-type HPV 16 E6 and E6 mutants compet
ent for p53 binding and degradation. A series of p53 deletions and hyb
rid proteins with heterologous DNA binding, dimerization and transacti
vation domains were analysed for transcriptional interaction with HPV
16 E6 to determine the domains of p53 required for transcriptional inh
ibition. These chimeric proteins were also analysed for E6 binding and
E6-mediated degradation in vitro. In both assays, complex formation w
ith E6 was mediated through the amino-terminal 345 amino acids of p53
without a specific requirement for its C-terminus. Hybrid proteins con
taining residues 161-345 of p53 also bound E6, but this segment of p53
was not susceptible to E6 induced proteolysis. A second region of p53
, within its N-terminal 160 aa, is required for E6 induced degradation
of complexed p53. Taken together, these results suggest that the comp
lex formation between E6 and p53 is not mediated through the C-terminu
s of p53 and that binding and degradation are separable.