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

J O Funk1, S Waga, J B Harry

  • 1Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

Genes & Development
|August 15, 1997
PubMed

Insights

Human papillomavirus (HPV) oncoprotein 16E7 disrupts cell cycle control by preventing p21 protein from inhibiting cyclin-dependent kinase (CDK) and DNA replication. This interaction overrides normal cell cycle regulation.

Area of Science:

  • Molecular Biology
  • Virology
  • Cell Cycle Regulation

Background:

  • p21 is a key cell cycle inhibitor, binding to cyclin-dependent kinases (CDKs) and proliferating cell nuclear antigen (PCNA) to halt DNA replication.
  • Human papillomavirus (HPV) oncoproteins, like HPV-16 E7 (16E7), are known to disrupt cell cycle control, promoting uncontrolled cell proliferation.

Purpose of the Study:

  • To investigate the mechanism by which HPV-16 E7 (16E7) abrogates cell cycle arrest despite high p21 levels.
  • To determine how 16E7 interacts with p21 to inhibit its functions.

Main Methods:

  • In vitro studies using cell lysates and purified proteins.
  • Analysis of interactions between 16E7, p21, CDK2/cyclin E, and PCNA.

Main Results:

  • HPV-16 E7 (16E7) prevents p21 from inhibiting CDK2/cyclin E activity and PCNA-dependent DNA replication.
  • The nononcogenic HPV-6 E7 showed reduced effects compared to 16E7.
  • 16E7 binds to the carboxy-terminal end of p21, overlapping with PCNA and cyclin-binding sites, thereby inactivating both inhibitory functions.

Conclusions:

  • The carboxyl terminus of p21 is crucial for modulating both CDK activity and PCNA-dependent DNA replication.
  • The HPV-16 E7 oncoprotein can override p21's regulatory functions by binding to its carboxyl terminus, leading to disruption of normal cell cycle control.

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