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Living with or without cyclins and cyclin-dependent kinases
Charles J Sherr1, James M Roberts
1Howard Hughes Medical Institute and Department of Genetics & Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. sherr@stjude.org
Genes & Development
|November 17, 2004
Summary
Mammalian cell cycle regulation by cyclin-dependent kinases (Cdks) is not strictly essential for fetal development, challenging long-held scientific beliefs. Recent studies show normal development occurs even when key Cdk genes are absent.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cyclin-dependent kinases (Cdks) complexed with D-type and E-type cyclins are traditionally considered essential for G1 phase progression in the mammalian cell cycle.
- Decades of research supported the view that these holoenzymes are critical for cell cycle control in response to mitogenic signals.
Purpose of the Study:
- To investigate the essentiality of D-type and E-type cyclins and their associated Cdks (Cdk2, Cdk4, Cdk6) in mammalian cell cycle progression.
- To reconcile conflicting findings between established dogma and recent genetic disruption experiments.
Main Methods:
- Germ line gene disruption in mice for all three D-type cyclins.
- Germ line gene disruption in mice for the two E-type cyclins.
- Germ line gene disruption in mice for cyclin-dependent kinases Cdk2, Cdk4, and Cdk6.
Main Results:
- Mice lacking all D-type cyclins, both E-type cyclins, Cdk2, Cdk4, or Cdk6 exhibited largely normal fetal development.
- These findings indicate that none of the studied genes are strictly essential for cell cycle progression during mammalian development.
Conclusions:
- The prevailing dogma regarding the absolute requirement of D-type/E-type cyclins and their Cdks for cell cycle progression needs re-evaluation.
- Further research is necessary to understand the compensatory mechanisms and the precise roles of these proteins in cell cycle control.