The dynamics of cyclin dependent kinase structure

doi:10.1016/S0955-0674(96)80076-7

Current Opinion in Cell Biology

Volume 8, Issue 6, December 1996, Pages 767-772

https://doi.org/10.1016/S0955-0674(96)80076-7 Get rights and content

Abstract

In the past year, several new crystal structures have provided exciting insights into the conformational changes underlying the regulation of cyclin-dependent kinases. We now understand the structural basis of many of the mechanisms by which cyclin-dependent kinases are regulated, including activation by cycling binding and phosphorylation, inhibition by the inhibitor p27, and binding by the CKS proteins.

References (29)

C Norbury et al.
Animal cell cycles and their control
Annu Rev Biochem
(1992)
DO Morgan
Principles of CDK regulation
Nature
(1995)
CJ Sherr et al.
Inhibitors of mammalian G1-cyclin-dependent kinases
Genes Dev
(1995)
E Lees
Cyclin dependent kinase regulation
Curr Opin Cell Biol
(1995)
JA Endicott et al.
The cell cycle and suc1: from structure to function?
Structure
(1995)
E Radzio-Andzelm et al.
Bound to activate: conformational consequences of cyclin binding to CDK2
Structure
(1995)
LN Johnson et al.
Active and inactive protein kinases: structural basis for regulation
Cell
(1996)
HL De Bondt et al.
Crystal structure of cyclin-dependent kinase 2
Nature
(1993)
NR Brown et al.
The crystal structure of cyclin A
Structure
(1995)
PD Jeffrey et al.
Mechanism of CDK activation revealed by the structure of a cyclin A-CDK2 complex
Nature
(1995)

L Connell-Crowley et al.

Phosphorylation-independent activation of human cyclin-dependent kinase 2 by cyclin A in vitro

Mol Biol Cell

(1993)

AA Russo et al.

Structural basis of cyclin-dependent kinase activation by phosphorylation

Nat Struct Biol

(1996)

D Desai et al.

The effect of phosphorylation by CAK on cyclin binding by CDC2 and CDK2

Mol Cell Biol

(1995)

AA Russo et al.

Crystal structure of the p27^Kip1 cyclin-dependent kinase inhibitor bound to the cyclinA—CDK2 complex

Nature

(1996)

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Spy1 is a novel cell cycle regulatory gene, which can control cell proliferation and survival through the atypical activation of cyclin-dependent kinases. Recent studies suggested that deregulation of Spy1 expression plays a key role in oncogenesis. To investigate the potential roles of Spy1 in hepatocellular carcinoma (HCC), expression of Spy1 was examined in human HCC samples.
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Cyclin E overexpression is observed in multiple human tumors and linked to poor prognosis. We have previously shown that ectopic expression of cyclin E is sufficient to induce mitogen-independent cell cycle entry in a variety of tumor/immortal cell lines. Here we have investigated the rate-limiting step leading to cell cycle entry in quiescent normal human fibroblasts (NHF) ectopically expressing cyclin E. We found that in serum-starved NHF, cyclin E forms inactive complexes with CDK2 and fails to induce DNA synthesis. Coexpression of SV40 small t antigen (st), but not other tested oncogenes, efficiently induces mitogen-independent CDK2 phosphorylation on Thr-160, CDK2 activation, and DNA synthesis. Additionally, in contact-inhibited NHF ectopically expressing cyclin E, st induces cell cycle entry, continued proliferation, and foci formation. Coexpression of cyclin E and st also bypasses G₀/G₁ arrests induced by CDK inhibitors. Although CDK2 is dispensable for G₀/G₁ cell cycle entry and normal proliferation in mammals, CDK2 activity is an essential rate-limiting step in NHF with deregulated cyclin E expression and altered PP2A activity, which endows primary cells with transformed features. Consequently, CDK2 could be targeted therapeutically in tumors that involve these alterations. These data also suggest that alterations prior to cyclin E deregulation facilitate proliferation of tumor cells by bypassing mitogenic requirements and negative regulation by adjacent cells.
Structure of the Pho85-Pho80 CDK-Cyclin Complex of the Phosphate-Responsive Signal Transduction Pathway
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Despite significant similarity between Pho85 and the cell-cycle CDKs, especially Cdc28/CDK2 (Toh-e et al., 1988), Pho85 possesses several important distinct features. Whereas phosphorylation of a conserved threonine or serine residue on the kinase subunit activation loop is required for full activation of CDK-cyclin complexes functioning in cell cycle (reviewed in Morgan, 1996 and Russo et al., 1996b), it is dispensable for Pho85-Pho80 kinase function (Nishizawa et al., 1999). The residue at the +3 position of the consensus sequence (S/TPXK/R, where S/T is the phosphorylatable residue and X is any residue) of the substrates of most cell-cycle CDK-cyclin complexes differs radically from that (SPXI/L) of the five phosphorylation sites on the Pho4 substrate of Pho85-Pho80 (O'Neill et al., 1996).
The ability to sense and respond appropriately to environmental changes is a primary requirement of all living organisms. In response to phosphate limitation, Saccharomyces cerevisiae induces transcription of a set of genes involved in the regulation of phosphate acquisition from the ambient environment. A signal transduction pathway (the PHO pathway) mediates this response, with Pho85-Pho80 playing a vital role. Here we report the X-ray structure of Pho85-Pho80, a prototypic structure of a CDK-cyclin complex functioning in transcriptional regulation in response to environmental changes. The structure revealed a specific salt link between a Pho85 arginine and a Pho80 aspartate that makes phosphorylation of the Pho85 activation loop dispensable and that maintains a Pho80 loop conformation for possible substrate recognition. It further showed two sites on the Pho80 cyclin for high-affinity binding of the transcription factor substrate (Pho4) and the CDK inhibitor (Pho81) that are markedly distant to each other and the active site.
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Several derivatives of the native Srb10 proteins from Saccharomyces cerevisiae and Kluyveromyces lactis, with removed selected motifs, have been constructed in order to test their role in Srb10p function. It has been demonstrated that the ATP binding site is necessary for repression of FLO11, CYC7 and SPI1. Yeast Srb10p specific motifs CM-I and CM-II, outside the kinase domain, are also necessary to complement two mutant phenotypes in S. cerevisiae Δsrb10 strains, the failure to growth in galactose at 37 °C and flocculation. They are also required to keep transcriptional repression of FLO11 in non-flocculants, and for aerobic repression of CYC7 and SPI1. Two-hybrid analyses revealed that, in Srb10p derivatives, the absence of these motifs decreases the interaction of Srb10p with its cyclin partner Srb11p and with the component Tup1p of the general co-repressor complex Tup1p–Ssn6p.
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Citation Excerpt :
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The dynamics of cyclin dependent kinase structure

Abstract

Animal cell cycles and their control

Annu Rev Biochem

Principles of CDK regulation

Nature

Inhibitors of mammalian G1-cyclin-dependent kinases

Genes Dev

Cyclin dependent kinase regulation

Curr Opin Cell Biol

The cell cycle and suc1: from structure to function?

Structure

Bound to activate: conformational consequences of cyclin binding to CDK2

Structure

Active and inactive protein kinases: structural basis for regulation

Cell

Crystal structure of cyclin-dependent kinase 2

Nature

The crystal structure of cyclin A

Structure

Mechanism of CDK activation revealed by the structure of a cyclin A-CDK2 complex

Nature

Phosphorylation-independent activation of human cyclin-dependent kinase 2 by cyclin A in vitro

Mol Biol Cell

Structural basis of cyclin-dependent kinase activation by phosphorylation

Nat Struct Biol

The effect of phosphorylation by CAK on cyclin binding by CDC2 and CDK2

Mol Cell Biol

Crystal structure of the p27Kip1 cyclin-dependent kinase inhibitor bound to the cyclinA—CDK2 complex

Nature

Crystal structure of the p27^Kip1 cyclin-dependent kinase inhibitor bound to the cyclinA—CDK2 complex