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PMID: 9284048 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein.

Genes & development ·Vol. 11 ·No. 16 ·1997-08-15 ·Pages 2090-100

Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA

Abstract

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.

MeSH Terms
Binding Sites CDC2-CDC28 Kinases Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinases/antagonists & inhibitors,genetics,metabolism Cyclins/drug effects,genetics,metabolism DNA Replication/drug effects Humans Keratinocytes/metabolism,virology Oncogene Proteins, Viral/genetics,metabolism Papillomavirus E7 Proteins Proliferating Cell Nuclear Antigen/metabolism,pharmacology Protein Serine-Threonine Kinases/genetics,metabolism Recombinant Proteins/genetics,metabolism
Chemicals
CDKN1A protein, human Cyclin-Dependent Kinase Inhibitor p21 Cyclins Oncogene Proteins, Viral Papillomavirus E7 Proteins Proliferating Cell Nuclear Antigen Recombinant Proteins oncogene protein E7, Human papillomavirus type 16 Protein Serine-Threonine Kinases CDC2-CDC28 Kinases CDK2 protein, human Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Funk J O
Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Waga S
Harry J B
Espling E
Stillman B
Galloway D A
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.11.16.2090
Published
1997-08-15
Pages
2090-100
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316456
Subset
IM
Grants
NCI NIH HHS · CA13106 · United States
NCI NIH HHS · CA64795 · United States
External Links
PubMed source DOI: 10.1101/gad.11.16.2090 PMC Full Text View journal details
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