Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p16 and p15 are representative members of cyclin-dependent kinase inhibitors. Because the selective expression of p57KIP2 in liver, and because p16CDKN2/MTS1/INK4A has been found altered in many primary tumors, we undertook the present study to determine the presence of alterations in these genes in a group of hepatocellular carcinomas (HCC). Seventeen tumor and normal DNA pairs were analyzed by Southern blot, PCR-SSCP and DNA sequencing. Microsatellite markers surrounding the area of the p16 gene was also used. Southern blot analysis did not show allelic losses of the p16 or p57KIP2 genes. In 4 cases, an extra band was observed when hybridizing with the specific p16 cDNA. Overall, 4/17 (24%) cases presented microsatellite alterations at the 9p21-24 region. These results suggest that deletions or point mutations in these genes are not frequent if present at all in HCC, but reveals the existence of microsatellite alterations at the 9p21-24 region in HCC.
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PMID:Mutational study of p16CDKN2/MTS1/INK4A and p57KIP2 genes in hepatocellular carcinoma. 947 96

We have previously shown that there were differential and dramatic decreases of cyclin and cyclin-dependent kinase (CDK) activities in cardiomyocytes during the neonatal period. The activity of CDKs control cell cycle progression, and this activity is regulated positively and negatively by association of CDKs with cyclins and cyclin-dependent kinase inhibitors (CKIs), respectively. While the INK family (p15(INK4B)/p16(INK4A)/p18(INK4C)/p19(INK4D)) of CKIs is not detectable in hearts, the KIP/CIP family (p21(CIP1), p27(KIP1) and p57(KIP2)) of CKIs is detectable in most organs including the heart. Differential and dramatic changes of the KIP/CIP family (p21(CIP1), p27(KIP1) and p57(KIP2)) of CKIs were detected in rat hearts during development. The mRNA and protein levels of p21(CIP1) and p57(KIP2) were readily detectable in hearts at gestational and early postnatal periods and decreased thereafter. The mRNA levels of p27(KIP1) in ventricles were high during the gestational period, and did not change until day 30 postnatal, then were decreased slightly in 90-day-old rats. The protein levels of p27(KIP1) increased significantly in the early postnatal period, then were expressed persistently, although levels decreased slightly in the adult period. However, protein levels of p27(KIP1) in atria did not change during development. Variable immuno-staining patterns of p27(KIP1) were observed at different periods of development and in various locations in myocardium. During the gestational period, approximately 35-50% of myocardial cells in the cardiac wall were p27(KIP1) immuno-positive and were distributed diffusely. These p27(KIP1) immunopositive cells increased predominantly in endocardial and mid-portion areas of ventricular myocardium at the early postnatal period. This heterogenous pattern of p27(KIP1) protein expression persisted to adult hearts though the percentage of p27(KIP1) immuno-positive cells decreased slightly. High magnification revealed that more than 50% of adult cardiomyocytes were p27(KIP1) immuno-positive and that p27(KIP1) was located solely in nuclei. These results indicate that p27(KIP1) may be an important inhibitor of CDK activities in cardiomyocytes during early postnatal development and may block the re-entrance of adult cardiomyocytes into the cell cycle after injury.
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PMID:Persistent and heterogenous expression of the cyclin-dependent kinase inhibitor, p27KIP1, in rat hearts during development. 951 24

Progression through the cell cycle is regulated in part by the sequential activation and inactivation of cyclin-dependent kinases (CDKs). Many signals arrest the cell cycle through inhibition of CDKs by CDK inhibitors (CKIs). p27(Kip1) (p27) was first identified as a CKI that binds and inhibits cyclin A/CDK2 and cyclin E/CDK2 complexes in G1. Here we report that p27 has an additional property, the ability to induce a proteolytic activity that cleaves cyclin A, yielding a truncated cyclin A lacking the mitotic destruction box. Other CKIs (p15(Ink4b), p16(Ink4a), p21(Cip1), and p57(Kip2)) do not induce cleavage of cyclin A; other cyclins (cyclin B, D1, and E) are not cleaved by the p27-induced protease activity. The C-terminal half of p27, which is dispensable for its kinase inhibitory activity, is required to induce cleavage. Mechanistically, p27 does not appear to cause cleavage through direct interaction with cyclin/CDK complexes. Instead, it activates a latent protease that, once activated, does not require the continuing presence of p27. Mutation of cyclin A at R70 or R71, residues at or very close to the cleavage site, blocks cleavage. Noncleavable mutants are still recognized by the anaphase-promoting complex/cyclosome pathway responsible for ubiquitin-dependent proteolysis of mitotic cyclins, indicating that the p27-induced cleavage of cyclin A is part of a separate pathway. We refer to this protease as Tsap (pTwenty-seven- activated protease).
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PMID:The cyclin-dependent kinase inhibitor p27(Kip1) induces N-terminal proteolytic cleavage of cyclin A. 986 Sep 76

Cyclin-dependent kinase inhibitory proteins are negative regulators of the cell cycle. Although all the cyclin-dependent kinase inhibitory proteins may be involved in cell cycle control during a differentiation process, only p57(Kip2) is shown to be essential for embryonic development. However, the role of p57 in the control of the cell cycle is poorly understood. Using osteoblasts derived from the calvaria of rat fetus, we show that p57 is accumulated in cells starved by low serum. Cyclin-dependent kinase 2 activity was suppressed in these cells with a significant amount bound to p57. Treatment of the cells with transforming growth factor beta1 dramatically reduced the amount of p57, resulting in an activation of cyclin-dependent kinase 2 activity and the stimulation of cell proliferation. The decrease in p57 was inhibited by treating the cells with proteasome inhibitors, Z-Leu-Leu-Leu-aldehyde or lactacystin, but not with Z-Leu-Leu-aldehyde, which is an inhibitor of calpain, indicating that p57 is degraded through the proteasome pathway. p57 was also shown to be ubiquitinated in vitro. Because transforming growth factor beta1 not only stimulates the growth but also inhibits the differentiation of the cells in this system, our results may suggest a possible involvement of p57 in the control of osteoblastic cell proliferation and differentiation.
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PMID:p57(Kip2) is degraded through the proteasome in osteoblasts stimulated to proliferation by transforming growth factor beta1. 1021 82

p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin/cyclin-dependent kinase (Cdk) complexes, and is a negative regulator of cell proliferation. The gene encoding p57KIP2 is located at 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome (BWS). Previously we demonstrated that p57KIP2 is imprinted and only the maternal allele is expressed in both mice and humans. We also showed mutations found in p57KIP2 in patients with BWS that were transmitted from the patients' carrier mothers, indicating that the expressed maternal allele was mutant and that the repressed paternal allele was normal. In the study reported here, we performed functional analysis of the two mutated p57KIP2 genes. We showed that the nonsense mutation found in the Cdk inhibitory domain in a BWS patient rendered the protein inactive with consequent complete loss of its role as a cell cycle inhibitor and of its nuclear localization. We also showed that the mutation in the QT domain, although completely retaining its cell cycle regulatory activity, lacked nuclear localization and was thus prevented from performing its role as an active cell cycle inhibitor. Consequently, no active p57KIP2 would have existed, which might have caused the disorders in BWS patients.
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PMID:Functional analysis of the p57KIP2 gene mutation in Beckwith-Wiedemann syndrome. 1032 43

Tamoxifen (Tam), besides its action as an anti-estrogen, also inhibits cell proliferation of estrogen receptor (ER)-negative cancer cells by an unknown mechanism. In this study, we used ER-negative lung cancer cells to clarify such ER-independent inhibitory effect of Tam. We found that Tam induced G1 growth arrest in these cells. However, our results indicated that the expression of G1 cyclins (including D1, 2, 3 and E) was not regulated by Tam in these lung cancer cells. Additionally, the protein levels of G1 acting cyclin-dependent kinases (CDKs), CDK2, 4 and 6, was unaltered in Tam-treated lung cancer cells with the exception of CDK2 expression in H322 cells which was attenuated by Tam in a cell line-specific manner. We next examined the effect of Tam on the expression of cyclin-dependent kinase inhibitors (CDKIs) and our results demonstrated that the expression of p21WAF1 and p27KIP1, but not p57KIP2, was strongly activated by Tam in these cells. The amounts of p21WAF1 and p27KIP1 co-immunoprecipitated with cyclin E were obviously increased after Tam treatment and reduced activity of cyclin E-associated kinases and accumulation of hypo-phosphorylated retinoblastoma (Rb) protein were clearly detected in Tam-incubated cells. No consentaneous induction of CDKIs was found when ER-negative lung cancer cells were incubated with cytotoxic drugs, cisplatin and etoposide, this indicates that enhancement of CDKI expression is not a non-specific effect of Tam. We also found that Tam may up-regulate p21WAF1 expression via transcription activation. Considered together, these results suggest that Tam-induced growth inhibition in ER-negative lung cancer cells is associated with induction of p21WAF1 and p27KIP1.
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PMID:Tamoxifen induces p21WAF1 and p27KIP1 expression in estrogen receptor-negative lung cancer cells. 1043 40

We show that expression of p57(Kip2), a potent tight-binding inhibitor of several G(1) cyclin-cyclin-dependent kinase (Cdk) complexes, increases markedly during C2C12 myoblast differentiation. We examined the effect of p57(Kip2) on the activity of the transcription factor MyoD. In transient transfection assays, transcriptional transactivation of the mouse muscle creatine kinase promoter by MyoD was enhanced by the Cdk inhibitors. In addition, p57(Kip2), p21(Cip1), and p27(Kip1) but not p16(Ink4a) induced an increased level of MyoD protein, and we show that MyoD, an unstable nuclear protein, was stabilized by p57(Kip2). Forced expression of p57(Kip2) correlated with hypophosphorylation of MyoD in C2C12 myoblasts. A dominant-negative Cdk2 mutant arrested cells at the G(1) phase transition and induced hypophosphorylation of MyoD. Furthermore, phosphorylation of MyoD by purified cyclin E-Cdk2 complexes was inhibited by p57(Kip2). In addition, the NH2 domain of p57(Kip2) necessary for inhibition of cyclin E-Cdk2 activity was sufficient to inhibit MyoD phosphorylation and to stabilize it, leading to its accumulation in proliferative myoblasts. Taken together, our data suggest that repression of cyclin E-Cdk2-mediated phosphorylation of MyoD by p57(Kip2) could play an important role in the accumulation of MyoD at the onset of myoblast differentiation.
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PMID:p57(Kip2) stabilizes the MyoD protein by inhibiting cyclin E-Cdk2 kinase activity in growing myoblasts. 1052 50

Transforming growth factor beta (TGF-beta)-mediated G(1) arrest previously has been shown to specifically target inactivation of cyclin D:cyclin-dependent kinase (Cdk) 4/6 complexes. We report here that TGF-beta-treated human HepG2 hepatocellular carcinoma cells arrest in G(1), but retain continued cyclin D:Cdk4/6 activity and active, hypophosphorylated retinoblastoma tumor suppressor protein. Consistent with this observation, TGF-beta-treated cells failed to induce p15(INK4b), down-regulate CDC25A, or increase levels of p21(CIP1), p27(KIP1), and p57(KIP2). However, TGF-beta treatment resulted in the specific inactivation of cyclin E:Cdk2 complexes caused by absence of the activating Thr(160) phosphorylation on Cdk2. Whole-cell lysates from TGF-beta-treated cells showed inhibition of Cdk2 Thr(160) Cdk activating kinase (CAK) activity; however, cyclin H:Cdk7 activity, a previously assumed mammalian CAK, was not altered. Saccharomyces cerevisiae contains a genetically and biochemically proven CAK gene, CAK1, that encodes a monomeric 44-kDa Cak1p protein unrelated to Cdk7. Anti-Cak1p antibodies cross-reacted with a 45-kDa human protein with CAK activity that was specifically down-regulated in response to TGF-beta treatment. Taken together, these observations demonstrate that TGF-beta signaling mediates a G(1) arrest in HepG2 cells by targeting Cdk2 CAK and suggests the presence of at least two mammalian CAKs: one specific for Cdk2 and one for Cdk4/6.
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PMID:Transforming growth factor beta targeted inactivation of cyclin E:cyclin-dependent kinase 2 (Cdk2) complexes by inhibition of Cdk2 activating kinase activity. 1061 20

Maternal loss of heterozygosity (LOH) of the 11p15 region and overexpression of the insulin-like growth factor (IGF)-II gene are associated with the malignant phenotype in sporadic adrenocortical tumors. In the imprinted 11p15 region, the p57KIP2 gene is maternally expressed and encodes a cyclin-dependent kinase (CDK) inhibitor involved in G1/S phase of the cell cycle. We hypothesized that maternal LOH in malignant adrenocortical tumors could be responsible for loss of p57KIP2 gene expression and, thus, could favor progression through the cell cycle. We investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal expression of the IGF-II gene (mainly benign) and 20 with IGF-II gene overexpression (mainly malignant)], and the human adrenocortical tumor cell line NCI H295R for expression of the p57KIP2 gene, G1 cyclins (cyclin D2 and E) and G1 CDK (CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin-CDK complexes. The expression of p57KIP2, G1 cyclins, and G1 CDKs in benign tumors was similar to that in normal adrenal tissues, as were kinase activities of G1 cyclin-CDK complexes. By contrast, abrogation of the p57KIP2 gene expression and increased expression of G1 cyclins (cyclin E) and G1 CDKs (CDK2 and CDK4) were associated with high activity of G1 cyclin-CDK complexes in malignant tumors and in the H295R cell line. These data suggest that the p57KIP2 gene might act as a tumor suppressor gene in adrenocortical tumors. Maternal LOH with duplication of the paternal allele or pathological functional imprinting of the 11p15 region are responsible for loss of expression of the p57KIP2 gene and increased expression of the IGF-II gene. Consequently, both events favor cell proliferation in malignant adrenocortical tumors.
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PMID:High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors. 1063 6

We previously uncovered that growth stimulation of rat primary osteoblasts by transforming growth factor-beta1 (TGF-beta1) resulted in a dramatic decrease in p57(Kip2), a member of cyclin-dependent kinase (CDK) inhibitors, through the proteasomal degradation pathway (Urano et al., J. Biol. Chem. 274, 12197-12200, 1999). Here we demonstrated that the amount of p57 protein increases markedly, when rat calvarial primary osteoblasts treated with 1,25-dihydroxyvitamin D3 transit from proliferation toward differentiation. Next, we have analyzed the association of four amino acids deletion polymorphism of p57 and bone mineral density (BMD). The p57 genotype was determined in 154 postmenopausal Japanese women. When we separated the subjects into two groups, one having one or two copies of deletion polymorphism and the other without the deletion, the former subjects had higher BMD (Z score of total body, 0.67 +/- 0.93 vs 0. 23 +/- 0.90, mean +/- standard deviation; P = 0.021). Taken together, these findings suggest that the p57 regulated in the osteoblast proliferation and differentiation may play a role in determination of bone mineral density and pathogenesis of osteoporosis.
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PMID:Possible involvement of the p57(Kip2) gene in bone metabolism. 1070 69


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