Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: EC:6.3.2.19 (
ubiquitin-protein ligase
)
799
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Degradation of the mammalian cyclin-dependent kinase (CDK) inhibitor p27 is required for the cellular transition from quiescence to the proliferative state. The ubiquitination and subsequent degradation of p27 depend on its phosphorylation by cyclin-CDK complexes. However, the
ubiquitin-protein ligase
necessary for p27 ubiquitination has not been identified. Here we show that the F-box protein SKP2 specifically recognizes p27 in a phosphorylation-dependent manner that is characteristic of an F-box-protein-substrate interaction. Furthermore, both in vivo and in vitro,
SKP2
is a rate-limiting component of the machinery that ubiquitinates and degrades phosphorylated p27. Thus, p27 degradation is subject to dual control by the accumulation of both
SKP2
and cyclins following mitogenic stimulation.
...
PMID:SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. 1055 16
Histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A arrest human papillomavirus (HPV)-positive carcinoma cells in G1 to S transition of the cell cycle, which is paralleled by an up-regulation of the cyclin-dependent kinase inhibitors (CKIs) p21CIP1 and p27KIP1 as well as the complete loss of cdk2 activity. Although HPV expression was hitherto thought to be required to maintain a proliferative phenotype of these cells, cdk2 suppression is achieved even in the presence of ongoing viral transcription. While CKIs normally cannot exert their cdk2-inhibitory function in the presence of the viral oncoprotein E7, co-immunoprecipitation experiments revealed that E7 binding is prevented. Increase of p27KIP1 correlates with down-regulation of p45SKP2, a component of the
ubiquitin-protein ligase
SCF(
SKP2
) controlling the half-life of regulatory proteins during the cell cycle. HDAC inhibition also triggered an E7-dependent degradation of pRb, while the levels of E2F remained unaffected. The presence of free intracellular E2F and the concomitant up-regulation of CKIs during G1 arrest results in a 'conflicting growth situation', which finally renders the cells to undergo apoptosis. These data provide novel molecular insights into how the transforming potential of HPV can be bypassed and open new therapeutical perspectives for the treatment of cervical cancer.
...
PMID:Inhibitors of histone deacetylase arrest cell cycle and induce apoptosis in cervical carcinoma cells circumventing human papillomavirus oncogene expression. 1152 Nov 89
F-Box protein p45(
SKP2
) is the substrate-specific receptor of
ubiquitin-protein ligase
SCF/p45(
SKP2
) and is involved in the degradation of p27(Kip1) through the ubiquitin/proteasome pathway. In addition, p45(
SKP2
) facilitates proteolysis of other molecules related to the cell cycle, is frequently over-expressed in transformed cells, and induces S phase in quiescent cells. The aim of this study was to determine whether p45(
SKP2
) expression is altered in aggressive lesions of Kaposi's sarcoma and its relation to p27(KIP1)down-regulation. We performed immunohistochemistry using antibodies directed to p45(
SKP2
), p27(KIP1), and Ki67 on paraffin blocks corresponding to 47 cases of Kaposi's sarcoma (8 macules, 10 plaques, 12 tumors, and 15 extracutaneous lesions). p45(
SKP2
) nuclear over-expression was present in all Kaposi's sarcoma stages, being significantly increased in skin tumors (mean +/- 95% confidence interval: 39.2 +/- 18.8) and extracutaneous lesions (25.8 +/- 17.3) as compared with macules (18.9 +/- 8.2) and plaques (29.2 +/- 12.0; P =.0199). On the other hand, Kaposi's sarcoma progression was associated with a decrease in p27(KIP1) expression and Ki67 immunoreactivity was independent of disease stage. No statistically significant differences were found in regard to patients' sex and human immunodeficiency virus status and regression analysis failed to show a correlation among p45(
SKP2
), p27(KIP1) and Ki67 immunostaining scores. These findings suggest that p45(
SKP2
) is involved in Kaposi's sarcoma progression, not only by promoting the degradation of p27(KIP1) but also through other mechanisms still unknown.
...
PMID:Over-expression of p45(SKP2) in Kaposi's sarcoma correlates with higher tumor stage and extracutaneous involvement but is not directly related to p27(KIP1) down-regulation. 1242 3
In SCF (Skp, Cullin, F-box)
ubiquitin-protein ligase
complexes, S-phase kinase 2 (
SKP2
) is one of the major players of F-box family, that is responsible for the degradation of several important cell regulators and tumor suppressor proteins. Despite of having significant evidence for the role of
SKP2
on tumorgenesis, there is a lack of available data regarding the effect of non-synonymous polymorphisms. In this communication, the structural and functional consequences of non-synonymous single nucleotide polymorphisms (nsSNPs) of
SKP2
have been reported by employing various computational approaches and molecular dynamics simulation. Initially, several computational tools like SIFT, PolyPhen-2, PredictSNP, I-Mutant 2.0 and ConSurf have been implicated in this study to explore the damaging SNPs. In total of 172 nsSNPs, 5 nsSNPs were identified as deleterious and 3 of them were predicted to be decreased the stability of protein. Guided from ConSurf analysis, P101L (rs761253702) and Y346C (rs755010517) were categorized as the highly conserved and functional disrupting mutations. Therefore, these mutations were subjected to three dimensional model building and molecular dynamics simulation study for the detailed structural consequences upon the mutations. The study revealed that P101L and Y346C mutations increased the flexibility and changed the structural dynamics. As both these mutations are located in the most functional regions of
SKP2
protein, these computational insights might be helpful to consider these nsSNPs for wet-lab confirmatory analysis as well as in rationalizing future population based studies and structure based drug design against
SKP2
.
...
PMID:Identification and structural characterization of deleterious non-synonymous single nucleotide polymorphisms in the human SKP2 gene. 3080 28
