Mechanism of Cdk2/Cyclin E Inhibition by p27 and p27 Phosphorylation

Xu, Xu; Nakano, Tatsuo; Wick, Scott; Dubay, Marja; Brizuela, Leonardo

doi:10.1021/bi9903446

Cited by 38 publications

(34 citation statements)

References 85 publications

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“…These results are consistent with prior observations that T187-phosphorylated p27 remains bound to and inhibits cyclin E/CDK2. 30,32 This supports previous reports which proposed p27 degradation, and not the phosphorylation event, is required for increased and maximal CDK2 activity.…”

Section: Spy1 Activates Cdk2 To Phosphorylate P27 On T187 In Vitrosupporting

confidence: 91%

“…Indeed, these results resemble previous work demonstrating phosphorylation of p27 at T187, and does not promote dissociation or relieve inhibition of the cyclin E/CDK2 complex. 30 Spy1 enhances cyclin E/CDK2 phosphorylation of p27. We hypothesized that Spy1 may also promote inhibited cyclin E/CDK2 to phosphorylate p27.…”

Section: Spy1 Activates Cdk2 To Phosphorylate P27 On T187 In Vitromentioning

confidence: 99%

“…30 We hypothesized that Spy1/CDK2 complexes could similarly phosphorylate p27 when bound to cyclin E/CDK2. To examine this, cyclin E, CDK2 D145N , and p27 were incubated for 20 min prior to the addition of preformed Spy1/CDK2 WT .…”

Section: Spy1 Activates Cdk2 To Phosphorylate P27 On T187 In Vitromentioning

confidence: 99%

“…3,[24][25][26][27][28] Free cyclin E/CDK2 was shown to phosphorylate p27 at T187 when bound to an inhibited, trimeric cyclin E/CDK2 complex. 29,30 CDK2-mediated phosphorylation of p27 at T187 targets it to SCF Skp2 complex for ubiquitin-dependent degradation during late G 1 /S phase. 29,[31][32][33][34][35][36][37][38][39][40][41][42] Subsequently, cyclin E/CDK2 becomes active which facilitates progression through S-phase.…”

Section: Introductionmentioning

confidence: 99%

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Spy1 Enhances Phosphorylation and Degradation of the Cell Cycle Inhibitor p27

McAndrew¹,

Gastwirt²,

Meyer³

et al. 2007

Cell Cycle

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Section: Spy1 Activates Cdk2 To Phosphorylate P27 On T187 In Vitrosupporting

confidence: 91%

Section: Spy1 Activates Cdk2 To Phosphorylate P27 On T187 In Vitromentioning

confidence: 99%

Section: Spy1 Activates Cdk2 To Phosphorylate P27 On T187 In Vitromentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spy1 Enhances Phosphorylation and Degradation of the Cell Cycle Inhibitor p27

McAndrew¹,

Gastwirt²,

Meyer³

et al. 2007

Cell Cycle

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“…Recent evidence suggests that the stability of p27 is dictated by its relative molar concentration with cyclin/CDK complexes. At high molar ratios, free cyclin E/CDK2 can phosphorylate p27 bound to cyclin E/CDK2, thus targeting p27 for destruction (Xu et al, 1999). Therefore, cAMP-mediated decreases in thyroid p27 protein levels might be indirectly regulated by increases in cyclin/CDK complexes.…”

Section: Discussionmentioning

confidence: 99%

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

et al. 2000

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p27 Kip1 (p27) controls cell cycle progression by binding to and inhibiting the activity of cyclin dependent kinases. Disruption of the p27 gene in mice (p277/7) results in increased body growth with a disproportionate enlargement of the spleen, thymus, testis, ovary and pituitary. The increase in pituitary size is due to selective hyperplasia of the intermediate lobe (IL) while the anterior lobe (AL) is not overtly a ected. p27 heterozygous mice (p27+/7), as well as p277/7 mice, are hypersensitive to radiation-and chemical-induced tumors compared to wildtype (p27+/+) littermates. Therefore, unlike classical tumor suppressors, only a reduction in p27 levels is necessary to predispose tissues to secondary tumor promoters. Consistent with these studies is the fact that the p27 gene sequence and mRNA levels appear normal in human pituitary adenomas while p27 protein levels are decreased. Therefore, a reduction in p27 levels could be su cient to sensitize pituitary cells to tumorigenic factors. To test this hypothesis, metallothionein promoter-driven, human growth hormone-releasing hormone (MT-hGHRH) transgenic mice, that exhibit somatotrope hyperplasia before 9 months of age and subsequent adenoma formation with 30 ± 40% penetrance, were crossbred with p27+/7 mice for two successive generations to produce p27+/+, p27+/7 and p277/7 mice that expressed the hGHRH transgene. At 10 ± 12 weeks of age, p277/7 and p27+/+, hGHRH mice were larger than their p27+/+ littermates and displayed characteristic hyperplasia of the IL and AL, respectively. Expression of the hGHRH transgene in both p27+/7 and p277/7 mice selectively expanded the population of somatotropes within the AL, where pituitaries of p27+/7, hGHRH and p277/7, hGHRH mice were two-and ®vefold larger than p27+/+, hGHRH pituitaries, respectively. There was also a synergistic e ect of hGHRH transgene expression and p27-de®ciency on liver, spleen and ovarian growth. At 6 ± 8 months of age, 83% of p27+/7, hGHRH mice displayed macroscopic AL adenomas (4100 mg), while all pituitaries from p27+/+, hGHRH mice remained hyperplastic (520 mg). In contrast to the dramatic e ects of p27-de®ciency on hGHRH-induced organ growth, elimination of p53, by crossbreeding MT-hGHRH mice to p53-de®cient mice, did not augment the hyperplastic/ tumorigenic e ects of hGHRH transgene expression.Taken together these results demonstrate that a reduction in p27 expression is su cient to sensitize somatotropes to the proliferative actions of excess GHRH, resulting in the earlier appearance and increased penetrance of hGHRH-induced pituitary tumors.

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Cell cycle regulatory protein p27^KIP1 is a substrate and interacts with the protein kinase CK2

Tapia

Bolaños-García

Sayed

et al. 2004

J of Cellular Biochemistry

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The protein kinase CK2 is constituted by two catalytic (alpha and/or alpha') and two regulatory (beta) subunits. CK2 phosphorylates more than 300 proteins with important functions in the cell cycle. This study has looked at the relation between CK2 and p27(KIP1), which is a regulator of the cell cycle and a known inhibitor of cyclin-dependent kinases (Cdk). We demonstrated that in vitro recombinant Xenopus laevis CK2 can phosphorylate recombinant human p27(KIP1), but this phosphorylation occurs only in the presence of the regulatory beta subunit. The principal site of phosphorylation is serine-83. Analysis using pull down and surface plasmon resonance (SPR) techniques showed that p27(KIP1) interacts with the beta subunit through two domains present in the amino and carboxyl ends, while CD spectra showed that p27(KIP1) phosphorylation by CK2 affects its secondary structure. Altogether, these results suggest that p27(KIP1) phosphorylation by CK2 probably involves a docking event mediated by the CK2beta subunit. The phosphorylation of p27(KIP1) by CK2 may affect its biological activity.

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Mechanism of Cdk2/Cyclin E Inhibition by p27 and p27 Phosphorylation

Cited by 38 publications

References 85 publications

Spy1 Enhances Phosphorylation and Degradation of the Cell Cycle Inhibitor p27

Spy1 Enhances Phosphorylation and Degradation of the Cell Cycle Inhibitor p27

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

Cell cycle regulatory protein p27^KIP1 is a substrate and interacts with the protein kinase CK2

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Mechanism of Cdk2/Cyclin E Inhibition by p27 and p27 Phosphorylation

Cited by 38 publications

References 85 publications

Spy1 Enhances Phosphorylation and Degradation of the Cell Cycle Inhibitor p27

Spy1 Enhances Phosphorylation and Degradation of the Cell Cycle Inhibitor p27

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

Cell cycle regulatory protein p27KIP1 is a substrate and interacts with the protein kinase CK2

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Cell cycle regulatory protein p27^KIP1 is a substrate and interacts with the protein kinase CK2