Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors.

Molecular and Cellular Biology
P D AdamsW G Kaelin

Abstract

Understanding how cyclin-cdk complexes recognize their substrates is a central problem in cell cycle biology. We identified an E2F1-derived eight-residue peptide which blocked the binding of cyclin A and E-cdk2 complexes to E2F1 and p21. Short peptides spanning similar sequences in p107, p130, and p21-like cdk inhibitors likewise bound to cyclin A-cdk2 and cyclin E-cdk2. In addition, these peptides promoted formation of stable cyclin A-cdk2 complexes in vitro but inhibited the phosphorylation of the retinoblastoma protein by cyclin A- but not cyclin B-associated kinases. Mutation of the cyclin-cdk2 binding motifs in p107 and E2F1 likewise prevented their phosphorylation by cyclin A-associated kinases in vitro. The cdk inhibitor p21 was found to contain two functional copies of this recognition motif, as determined by in vitro kinase binding/inhibition assays and in vivo growth suppression assays. Thus, these studies have identified a cyclin A- and E-cdk2 substrate recognition motif. Furthermore, these data suggest that p21-like cdk inhibitors function, at least in part, by blocking the interaction of substrates with cyclin-cdk2 complexes.

References

Jan 1, 1992·Annual Review of Biochemistry·C Norbury, P Nurse
Feb 14, 1992·Biochemical and Biophysical Research Communications·F ZindyC Bréchot
Sep 20, 1991·Cell·T Hunter, J Pines
Aug 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·I A WilsonS Brenner
Aug 1, 1987·Molecular and Cellular Biology·C Chen, H Okayama
Oct 24, 1995·Proceedings of the National Academy of Sciences of the United States of America·J Y SuJ L Maller
Dec 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·J Y Kato, C J Sherr
Aug 1, 1995·The Biochemical Journal·J SrinivasanD S Lawrence
May 1, 1995·Molecular and Cellular Biology·M OhtsuboM Pagano
May 15, 1995·Genes & Development·C J Sherr, J M Roberts
Jul 1, 1995·Molecular and Cellular Biology·D Resnitzky, S I Reed
Jan 1, 1995·Molecular and Cellular Biology·E J Smith, J R Nevins
Feb 1, 1995·Molecular and Cellular Biology·X Q QinW G Kaelin
Mar 9, 1995·Nature·D O Morgan
Aug 1, 1994·Genes & Development·H ZhangD Beach
Aug 1, 1994·Genes & Development·B D DynlachtE Harlow
Aug 16, 1994·Proceedings of the National Academy of Sciences of the United States of America·E A MusgroveR L Sutherland
Mar 1, 1994·Molecular and Cellular Biology·H MatsushimeJ Y Kato

❮ Previous
Next ❯

Citations

Jun 10, 2000·Molecular and Cellular Biology·F R Cross, M D Jacobson
Jan 12, 2000·The Journal of Cell Biology·K J HarveyD S Ucker
Jun 24, 2000·Molecular and Cellular Biology·G L BondJ L Manley
Oct 12, 2000·Molecular and Cellular Biology·S N AvedisovB J Thomas
Sep 27, 2001·Proceedings of the National Academy of Sciences of the United States of America·M WeinreichB Stillman
May 22, 2001·The Journal of Biological Chemistry·T Zhang, C Prives
Oct 19, 2001·Molecular Biology and Evolution·S N AvedisovB J Thomas
Jul 14, 2001·Molecular Biology of the Cell·T Y Kim, W G Kaelin
Mar 9, 2002·Molecular and Cellular Biology·Xiaohong LengJ Wade Harper
Oct 3, 2001·The Journal of Biological Chemistry·O W PrallR L Sutherland
Oct 18, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·D I ZhelevaD P Lane
Mar 16, 2004·The Journal of Biological Chemistry·Bérangère DubourgNazanine Modjtahedi
Jul 12, 2005·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Damien SoghoianThottala Jayaraman
Nov 9, 2005·Proceedings of the National Academy of Sciences of the United States of America·Gaétan BourCécile Rochette-Egly
Dec 24, 2005·EMBO Reports·Douglas MarkhamNicholas B La Thangue
Sep 19, 2006·Nature Structural & Molecular Biology·Yong TangRonen Marmorstein
Mar 22, 2007·Proteins·Graziano Lolli, Louise N Johnson
Sep 6, 2007·PLoS Genetics·Jeremy O WardJohn C Schimenti
Jun 30, 2007·The Journal of Biological Chemistry·Adrian PeresLieven De Veylder
Jan 24, 2007·Molecular and Cellular Biology·Rugang ZhangPeter D Adams
Oct 19, 2007·Molecular Biology of the Cell·Ande SatyanarayanaPhilipp Kaldis
Mar 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·Qiuming KanHiroto Okayama
Oct 15, 1998·Proceedings of the National Academy of Sciences of the United States of America·K Cai, B D Dynlacht
Jul 22, 1998·Molecular and Cellular Biology·W SeghezziE Lees
Sep 2, 1998·Proceedings of the National Academy of Sciences of the United States of America·B A SchulmanE Harlow
Aug 26, 1998·Molecular and Cellular Biology·E CastañoB D Dynlacht
May 20, 1999·Annual Review of Pharmacology and Toxicology·D G Johnson, C L Walker
Nov 9, 2000·The Journal of Biological Chemistry·D Y TakedaA Dutta
Aug 10, 2000·The Journal of Biological Chemistry·P KaldisM J Solomon
Jul 4, 2001·Nature Cell Biology·H M ChanN B La Thangue
Jan 16, 2002·Journal of Biomolecular Structure & Dynamics·Y H SungW Lee

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Cycle Pathways

Cell cycle is a complex process regulated by several signal transduction pathways and enzymes. Here is the latest research on regulation of cell cycle and cell cycle pathways.

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.