Crystal Structure of a Conformation-selective Casein Kinase-1 Inhibitor

Mashhoon, Neda; Demaggio, Anthony J.; Tereshko, Valentina; Bergmeier, Stephen C.; Egli, Martin; Hoekstra, Merl F.; Kuret, Jeff

doi:10.1074/jbc.m001713200

Cited by 134 publications

(146 citation statements)

References 53 publications

Supporting

Mentioning

135

Contrasting

Order By: Relevance

“…To determine whether IC261 can affect p53 phosphorylation on other sites under these conditions, the experiment was repeated but the phosphorylation on Ser15 was examined instead. Unlike the effect on Thr18 phosphorylation, IC261 had no effect on Ser15 phosphorylation (Figure 3b), supporting the specificity of IC261 to CK1d/ e (Mashhoon et al, 2000). This result strongly supports a role for CK1d/e in the phosphorylation of p53 on Thr18 in vivo in response to DNA damage.…”

Section: Resultssupporting

confidence: 66%

“…To determine whether CK1d/e is responsible for the observed Thr18 phosphorylation of p53 in NB4 cells, the extent of phosphorylation was compared in the presence or absence of the CK1d/e specific inhibitor, IC261 (Knippschild et al, 1997;Behrend et al, 2000;Mashhoon et al, 2000). NB4 cells were exposed to IR (5 Gy) together with As 2 O 3 (1 mM) for 10 min in the absence or the presence of increasing amounts of IC261.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

PML enhances the regulation of p53 by CK1 in response to DNA damage

et al. 2008

View full text Add to dashboard Cite

In response to stress, p53 is accumulated and activated to induce appropriate growth inhibitory responses. This requires the release of p53 from the constraints of its negative regulators Mdm2 and Mdm4. A key event in this dissociation is the phosphorylation of p53 at threonine residue (Thr18) within the Mdm2/4-binding domain. Casein kinase 1 (CK1) plays a major role in this phosphorylation. The promyelocytic leukemia protein (PML) regulates certain modifications of p53 in response to DNA damage. Here, we investigated the role of PML in the regulation of Thr18 phosphorylation. We found that PML enhances Thr18 phosphorylation of endogenous p53 in response to stress. On DNA damage, CK1 accumulates in the cell, with a proportion concentrated in the nucleus together with p53 and PML. Furthermore, CK1 interacts with endogenous p53 and PML, and this interaction is enhanced by genotoxic stress. Inhibition of CK1 impairs the protection of p53 by PML from Mdm2-mediated degradation. Our findings support a role for PML in the regulation of p53 by CK1. We propose that following DNA damage, PML facilitates Thr18 phosphorylation by recruiting p53 and CK1 into PML nuclear bodies, thereby protecting p53 from inhibition by Mdm2, leading to p53 activation.

show abstract

Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

PML enhances the regulation of p53 by CK1 in response to DNA damage

et al. 2008

View full text Add to dashboard Cite

show abstract

“…To date several CKI inhibitors are known (Rena et al, 2004), one of which is IC261, an ATP-competitive inhibitor that is selective for CKId and CKIe (Mashhoon et al, 2000). Other two known inhibitors are D4476 and CKI-7.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility

Garzia¹,

D’Angelo²,

Amoresano

et al. 2007

Oncogene

View full text Add to dashboard Cite

The combination of an increase in the cAMP-phosphodiesterase activity of h-prune and its interaction with nm23-H1 have been shown to be key steps in the induction of cellular motility in breast cancer cells. Here we present the molecular mechanisms of this interaction. The region of the nm23-h-prune interaction lies between S120 and S125 of nm23, where missense mutants show impaired binding; this region has been highly conserved throughout evolution, and can undergo serine phosphorylation by casein kinase I. Thus, the casein kinase I d-e specific inhibitor IC261 impairs the formation of the nm23-hprune complex, which translates 'in vitro' into inhibition of cellular motility in a breast cancer cellular model. A competitive permeable peptide containing the region for phosphorylation by casein kinase I impairs cellular motility to the same extent as IC261. The identification of these two modes of inhibition of formation of the nm23-H1-h-prune protein complex pave the way toward new challenges, including translational studies using IC261 or this competitive peptide 'in vivo' to inhibit cellular motility induced by nm23-H1-h-prune complex formation during progression of breast cancer.

show abstract

“…Moreover, IC261 shows an order of magnitude higher selectivity for CK1d and CK1e over other CK1 isoforms. The basis of CK1 speci®city has been established at 2.8 A resolution by X-ray crystallography (Mashhoon et al, 2000).…”

Section: Effects Of Ic261 On Cell Cycle Distribution and Cell Survivamentioning

confidence: 99%

“…In the present paper we describe the e ect of an ATP-competitive inhibitor IC261 with di erential activities among CK1 isoforms (Mashhoon et al, 2000) in a wild-type or mutant p53 containing tumor cell line (MethAtsp53 cells) as well as in p53 wild-type (+/+ MEFs), p53 plus-minus (+/7 MEFs) and p53-null mouse embryo ®broblasts (7/7 MEFs). After p53-independent mitotic delay IC261 induces a p53-dependent G1 arrest.…”

Section: Introductionmentioning

confidence: 99%

IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects

et al. 2000

View full text Add to dashboard Cite

The p53-targeted kinases casein kinase 1d (CK1d) and casein kinase 1e (CK1e) have been proposed to be involved in regulating DNA repair and chromosomal segregation. Recently, we showed that CK1d localizes to the spindle apparatus and the centrosomes in cells with mitotic failure caused by DNA-damage prior to mitotic entry. We provide here evidence that 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), a novel inhibitor of CK1d and CK1e, triggers the mitotic checkpoint control. At low micromolar concentrations IC261 inhibits cytokinesis causing a transient mitotic arrest. Cells containing active p53 arrest in the postmitotic G1 phase by blockage of entry into the S phase. Cells with non-functional p53 undergo postmitotic replication developing an 8N DNA content. The increase of DNA content is accompanied by a high amount of micronucleated and apoptotic cells. Immun¯uorescence images show that at low concentrations IC261 leads to centrosome ampli®cation causing multipolar mitosis. Our data are consistent with a role for CK1d and CK1e isoforms in regulating key aspects of cell division, possibly through the regulation of centrosome or spindle function during mitosis. Oncogene (2000) 19, 5303 ± 5313.

show abstract

Crystal Structure of a Conformation-selective Casein Kinase-1 Inhibitor

Cited by 134 publications

References 53 publications

PML enhances the regulation of p53 by CK1 in response to DNA damage

PML enhances the regulation of p53 by CK1 in response to DNA damage

Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility

IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects

Contact Info

Product

Resources

About