A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4

@article{Serrano1993ANR,
  title={A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4},
  author={M Serrano and Gregory J. Hannon and David H. Beach},
  journal={Nature},
  year={1993},
  volume={366},
  pages={704-707}
}
THE division cycle of eukaryotic cells is regulated by a family of protein kinases known as the cyclin-dependent kinases (CDKs)1,2. The sequential activation of individual members of this family and their consequent phosphorylation of critical substrates promotes orderly progression through the cell cycle3,4. The complexes formed by CDK4 and the D-type cyclins have been strongly implicated in the control of cell proliferation during the G1 phase3–6. CDK4 exists, in part, as a multi-protein… 
View on Nature
cancan.cshl.edu
3,873 Citations
Highly Influential Citations
134
Background Citations
1,290
Methods Citations
72
Results Citations
22

3,873 Citations

Chapter 25. Cell Cycle Control and Cancer

Regulation and Function of a Cell Cycle Key Regulator

A comprehensive review of current knowledge on p27 functions as a positive and negative regulator of G1 phase progression that could make it an attractive candidate as a therapeutical target.

Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors.

The structure reveals that p18(INK4c) inhibits the CDK-cyclin complex by distorting the ATP binding site and misaligning catalytic residues, and this structure provides insights into the specificity of the D-type cyclins for Cdk4/6.

Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb.

It is reported that the p16 mRNA accumulates to a high level in cells lacking pRb function and transcription of p16 is repressed by pR b, providing evidence supporting a feedback regulatory loop involving pRB, p16, and cyclin-dependent kinases.

The Cyclin/Cyclin-Dependent Kinase (cdk) Complex: Regulation of Cell Cycle Progression and Nuclear Disassembly

Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes.

It is shown that phosphorylation of the pRb-related p107 results in the loss of the ability to associate with E2F-4, a transcription factor with growth-promoting and oncogenic activity, and that the activity of p107 is regulated by phosphorylated through D-type cyclins.

Formation of p27-CDK complexes during the human mitotic cell cycle.

  • T. SoosH. Kiyokawa A. Koff
  • Biology
    Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
  • 1996
It is reported that, in MANCA cells, the amount of p27 is constant during the cell cycle and this data are consistent with a model wherein cyclin D/CDK complexes sequester the CDK2-dependent kinase inhibitory activity of p 27.

Conditional binding to and cell cycle-regulated inhibition of cyclin-dependent kinase complexes by p27Kip1.

Evidence is provided for cross-talk between the acquisition of quiescence, cdk activity, and G1 traverse and the results suggest an interplay between these two cell cycle transitions.

Regulation of CDK7–Carboxyl-Terminal Domain Kinase Activity by the Tumor Suppressor p16INK4A Contributes to Cell Cycle Regulation

The results suggest that p16INK4A may regulate cell cycle progression by inhibiting not only CDK4-pRb kinase activity but also by modulating CDK7-CTD kinases activity.

Advances in Brief Transcriptional Repression of the D-Type Cyclin-dependent Kinase Inhibitor p 16 by the Retinoblastoma Susceptibility Gene Product pRbt

It is reported that the p16 mRNA accumulates to a high level in cells lacking pRb function and transcription ofpl6 is repressed by pR b, providing evidence supporting a feedback regulatory loop involving pRB, p16, and cydin-dependent kinases.
...

References

SHOWING 1-10 OF 22 REFERENCES

p21 is a universal inhibitor of cyclin kinases

It is found that over expression of p21 inhibits the activity of each member of the cyclin/CDK family, and this results indicate that p21 may be a universal inhibitor of cyclin kinases.

D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA

Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation.

The pattern of subunit rearrangement of cyclin-CDK complexes in SV40-transformed cells is also shared in those containing adeno- or papilloma viral oncoproteins, and this findings suggest a mechanism by which oncogenic proteins alter the cell cycle of transformed cells.

Functional interactions of the retinoblastoma protein with mammalian D-type cyclins

Functional analysis of the P box, a domain in cyclin B required for the activation of Cdc25

Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle

Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase

The approach was to map the regions required on the cyclin A molecule for interaction with cdc2 to two small noncontiguous stretches of amino acids, both located within the conserved cyclin box domain of the protein, which suggests that the Cyclin family members may have conserved a similar mechanism to bind and activate cyclin-dependent kinases.

A family of human cdc2‐related protein kinases.

Ten human protein kinases based on their structural relation to p34cdc2 are identified, opening the possibility of combinatorial regulation of the cell cycle together with the emerging large family of cyclins.

Isolation of the Rb-related p130 through its interaction with CDK2 and cyclins.

A two-hybrid protein interaction screen was used to isolate cDNAs encoding human proteins that can interact with human CDK2 in yeast, and a new member of the retinoblastoma susceptibility gene family, Rbr-2 (Rb-related), was obtained, indicating it is the adenovirus E1A-associated p130.

Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein.

It is shown that, like pRB, p107 is a potent inhibitor of E2F-mediated trans-activation, and overexpression of p107 can inhibit proliferation in certain cell types, arresting sensitive cells in G1.