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1 Program in Cancer Biology, Fred Hutchinson Cancer
Research Center (FHCRC), Seattle, Washington 98109 USA;
2 Cold
Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 USA
p21 inhibits cyclin-dependent kinase (CDK) activity and
proliferating cell nuclear antigen (PCNA)-dependent DNA replication by
binding to CDK/cyclin complexes and to PCNA through
distinct domains. The human papillomavirus (HPV)-16 E7 oncoprotein
(16E7) abrogated a DNA damage-induced cell cycle arrest in vivo,
despite high levels of p21. Using cell lysates and purified proteins we show that 16E7 prevented p21 both from inhibiting
CDK2/cyclin E activity and PCNA-dependent DNA
replication, whereas the nononcogenic HPV-6 E7 had reduced effects.
Inactivation of both inhibitory functions of p21 was attained through
binding between 16E7 and sequences in the carboxy-terminal end of p21
that overlap with the PCNA-binding site and the second p21
cyclin-binding motif. These data imply that the carboxyl terminus of
p21 simultaneously modulates both CDK activity and PCNA-dependent DNA
replication and that a single protein, 16E7, can override this
modulation to disrupt normal cell cycle control.
[Key Words: CDK inhibitors; p21CIP1/WAF1/SDI1; DNA replication; PCNA; cell cycle arrest; HPV-16 E7; HPV-6 E7]
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