Rapid Degradation of the G
            <sub>1</sub>
            Cyclin Cln2 Induced by CDK-Dependent Phosphorylation

Lanker, Stefan; Valdivieso, M.‐Henar; Wittenberg, Curt

doi:10.1126/science.271.5255.1597

Cited by 221 publications

(209 citation statements)

References 25 publications

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“…If degradation of p27 has similarities to the degradation of G1 cyclins in S. cerevisiae, our observations may be equivalent to the recognition of phosphorylated Cln2 by a Cdc53/Cdc34/Cdc4 complex which precedes its degradation (e.g. Bai et al, 1996;Lanker et al, 1996;Willems et al, 1996). In this sense, the Myc-dependent sequestration' of p27 reported by Amati and colleagues may refer to the formation of a similar complex (Vlach et al, 1996).…”

Section: Discussionsupporting

confidence: 55%

Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

Müller¹,

Bouchard²,

et al. 1997

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Activation of Myc triggers a rapid induction of cyclin E/ cdk2 kinase activity and degradation of p27. Overt degradation of p27 is preceded by a speci®c dissociation of p27 from cyclin E/cdk2, but not from cyclin D/cdk4 complexes. We now show that cyclin E/cdk2 phosphorylates p27 at a carboxy-terminal threonine residue (T187) in vitro; mutation of this residue to valine stabilises cyclin E/cdk2 complexes. This reaction is not signi®cantly inhibited by high concentrations of p27, suggesting that cdk2 bound to p27 is catalytically active. In vivo, p27 bound to cyclins E and A, but not to D-type cyclins is phosphorylated. Myc-induced release of p27 from cdk2 requires cdk2 kinase activity and is delayed in a T187V mutant of p27. After induction of Myc, p27 phosphorylated at threonine 187 transiently accumulates in a non cdk2 bound form. Our data suggest a mechanism in which p27 is released from cyclin E/cdk2 upon phosphorylation; in Myc-transformed cells, release is e cient as phosphorylated p27 is transiently bound in a non-cdk2 containing complex and subsequently degraded.

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Section: Discussionsupporting

confidence: 55%

Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

Müller¹,

Bouchard²,

et al. 1997

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“…BLM contains an L2G box (amino-acids 406 ± 432) which could serve as an E6-AP speci®c substrate recognition site for ubiquitination, as described for the Mcm7 protein (KuÈ hne and Banks, 1998). Furthermore, uctuations of BLM levels during the cell cycle were evocative of a protein degraded through the ubiquitin- proteasome pathway, similar to geminin, an inhibitor of DNA replication (McGarry and Kirschner, 1998), and several cases of phosphorylation promoting ubiquitination have been described (i.e., see Clurman et al, 1996;Lanker et al, 1996). We thus asked the question whether BLM could be targeted for degradation through a ubiquitin conjugation process.…”

Section: Discussionmentioning

confidence: 99%

Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

et al. 2000

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Bloom's syndrome (BS) is a rare human autosomal recessive disorder characterized by an increased risk to develop cancer of all types. BS cells are characterized by a generalized genetic instability including a high level of sister chromatid exchanges. BS arises through mutations in both alleles of the BLM gene which encodes a 3' ± 5' DNA helicase identi®ed as a member of the RecQ family. We developed polyclonal antibodies speci®c for the NH 2 -and COOH-terminal region of BLM. Using these antibodies, we analysed BLM expression during the cell cycle and showed that the BLM protein accumulates to high levels in S phase, persists in G2/ M and sharply declines in G1, strongly suggestive of degradation during mitosis. The BLM protein is subject to post-translational modi®cations in mitosis, as revealed by slow migrating forms of BLM found in both demecolcine-treated cells and in mitotic cells isolated from non-treated asynchronous populations. Phosphatase treatment indicated that phosphorylation events were solely responsible for the appearance of the retarded moieties, a possible signal for subsequent degradation. Together, these results are consistent with a role of BLM in a replicative (S phase) and/or post-replicative (G2 phase) process.

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“…Over the last few years it has become clear that phosphorylation plays an important regulatory role in the degradation of a number of proteins (for example see, Nishizawa et al, 1992;Chen et al, 1995;Lanker et al, 1996;Skowyra et al, 1997). p53 is a well known phosphoprotein which contains a number of phosphorylation sites in the N-terminal as well as in the Cterminal region (Steegenga et al, 1996;Meek et al, 1997), and it has been reported that mutation of the known phosphorylation sites at positions 15 and 315 a ects the p53 turnover rate (Fiscella et al, 1993;Lin and Desiderio, 1993).…”

Section: Introductionmentioning

confidence: 99%

Characterization of sequence elements involved in p53 stability regulation reveals cell type dependence for p53 degradation

et al. 1998

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The growth suppressive properties of the tumor suppressor protein p53 are activated upon DNA damage. The activation of p53 is re¯ected in increased p53 levels which are, at least in part, the result of an extended halflife of the protein. Although this suggests that stabilization of p53 is an intrinsic feature of p53 activation, the mechanisms involved in p53 degradation and stabilization are poorly understood. Here we report on the identi®ca-tion of an internal deletion mutant of wild-type p53, termed D62 ± 96, which can be stably expressed in various cell lines. This deletion mutant has a turnover rate similar to wild-type p53 and its stability is upregulated by treatment with UV light. In cell lines that express endogenous mutant or no p53, however, D62 ± 96 appears to be stable, strongly indicating that these cell lines have lost the ability to degrade p53. Further characterization of D62 ± 96 by mutational analyses de®nes sequence and structural requirements for p53 degradation and indicates that none of the known p53 phosphorylation sites is essential with respect to p53 stability regulation upon UV-irradiation.

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Rapid Degradation of the G ₁ Cyclin Cln2 Induced by CDK-Dependent Phosphorylation

Cited by 221 publications

References 25 publications

Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

Characterization of sequence elements involved in p53 stability regulation reveals cell type dependence for p53 degradation

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Rapid Degradation of the G 1 Cyclin Cln2 Induced by CDK-Dependent Phosphorylation

Cited by 221 publications

References 25 publications

Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

Characterization of sequence elements involved in p53 stability regulation reveals cell type dependence for p53 degradation

Contact Info

Product

Resources

About

Rapid Degradation of the G ₁ Cyclin Cln2 Induced by CDK-Dependent Phosphorylation