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)

During meiotic maturation or after fertilization of invertebrate and vertebrate oocytes, many of the quiescent stored mRNAs are recruited into polysomes. In the clam, Spisula solidissima, such masked messages include the abundant mRNAs encoding cyclin A and the small subunit of ribonucleotide reductase. We have previously shown that mRNA-specific unmasking of these two messages can be achieved in vitro, in oocyte cell-free extracts, by the addition of antisense RNAs corresponding to a fairly short (130-140 nucleotides) segment in their cognate 3' untranslated regions. We postulated that the antisense RNAs prevented the binding of a masking repressor protein (Standart et al., 1990). Here we report UV-crosslinking and gel retardation studies which show that the masking portions of the translationally regulated mRNAs bind an oocyte protein of 82 kDa (p82), which is phosphorylated after fertilization. This modification was accompanied by altered RNP complex formation in gel retardation assays. These changes presumably reflect the activation of translation of the masked mRNAs. The role of p82 phosphorylation in maternal mRNA unmasking was assessed in a novel in vitro activation system developed from clam oocytes, based upon the natural rise in pH which accompanies fertilization. Concomitant with mRNA unmasking, several kinases, including cdc2 and MAP kinases were activated in this system, as was p82 phosphorylation. Inhibitors of serine/threonine kinases, including 6-DMAP, staurosporine, and H7 inhibited p82 phosphorylation, whereas inhibitors of tyrosine kinases, protein kinase C, cAMP-dependent protein kinase, and p70s6k did not prevent this modification. A specific inhibitor of cdc2 kinase, p27Kip1, prevented p82 phosphorylation and translational activation, strongly suggesting that p82 modification is required for unmasking.
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PMID:Unmasking mRNA in clam oocytes: role of phosphorylation of a 3' UTR masking element-binding protein at fertilization. 857 30

Cells deprived of serum mitogens will either undergo immediate cell cycle arrest or complete mitosis and arrest in the next cell cycle. The transition from mitogen dependence to mitogen independence occurs in the mid-to late G1 phase of the cell cycle and is called the restriction point. Murine Balb/c-3T3 fibroblasts deprived of serum mitogens accumulated the cyclin-dependent kinase (CDK) inhibitor p27Kip1. This was correlated with inactivation of essential G1 cyclin-CDK complexes and with cell cycle arrest in G1. The ability of specific mitogens to allow transit through the restriction point paralleled their ability to down-regulate p27, and antisense inhibition of p27 expression prevented cell cycle arrest in response to mitogen depletion. Therefore, p27 is an essential component of the pathway that connects mitogenic signals to the cell cycle at the restriction point.
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PMID:Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle. 862 23

Cell proliferation control is ensured by a group of proteins named cyclin-dependent kinases (CDKs), the activation of which is dependent on phosphorylation and cyclin association. In parallel, these CDKs are negatively controlled by two distinct groups of inhibitory proteins, the cyclin-dependent kinase inhibitors (CKIs). The first group, including p16Ink4a, p15Ink4b, p18Ink4c and p19Ink4d, is specific for the G1 CDKs, CDK4 and CDK6, inhibiting the kinase activity of cyclin D/CDK4-CDK6 complexes on pRb. p16Ink4a, down-regulated by pRb, inhibits G1 CDKs by competition with cyclin D; p15Ink4b, the synthesis of which is induced by TGF beta, seems to be a mediator of TGF beta-mediated cell cycle arrest. Furthermore, p18Ink4c inhibits CDK6 phosphorylation and activation by CAK. The second CKIs family is constituted by p21Waf1, p27Kip1 and p57Kip2. Their inhibitory action concerns a large range of cyclin/CDK complexes involved in G1 and S phase. p21Waf1, induced in part by p53, is up-regulated by senescence, DNA damage and cellular differentiation. p21Waf1 forms quaternary complexes with CDKs, cyclins and PCNA. Its inhibitory action, preventing CDK from phosphorylation, depends on the stoichiometry of the components. As p15Ink4b, p27Kip1 causes late G1 cell cycle arrest after TGF beta treatment and contact inhibition. The implications of CKIs in hematological malignancies are function of deletions or mutations of their genes. p16Ink4a and p15Ink4b genes, localized on 9p21, present frequent homozygous deletions in ALL T, ATL and lymphoblastic acutisation of CML. The other CKIs present very rare homozygous deletions or mutations, particularly p21Waf1 and p27Kip2. However, reduction of inhibitory activity due to hemizygous deletions might favour leukemogenesis.
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PMID:Cyclin-dependent kinase inhibitors (CKIs) and hematological malignancies. 889 23

Terminal cell differentiation involves permanent withdrawal from the cell division cycle. The inhibitors of cyclin-dependent kinases (CDKs) are potential molecules functioning to couple cell cycle arrest and cell differentiation. In murine C2C12 myoblast cells, G1 CDK enzymes (CDK2, CDK4, and CDK6) associate with four CDK inhibitors: p18INK4c, p19INK4d, p21, and p27Kip1. During induced myogenesis, p21 and its associated CDK proteins underwent an initial increase followed by a decrease as cells became terminally differentiated. The level of p27 protein gradually increased, but the amount of total associated CDK proteins remained unchanged. p19 protein decreased gradually during differentiation, as did its associated CDK4 protein. In contrast, p18 protein increased 50-fold, from negligible levels in proliferating myoblasts to clearly detectable levels within 8-12 h of myogenic induction. This initial rise was followed by a precipitous increase between 12 and 24 h postinduction, with p18 protein finally accumulating to its highest level in terminally differentiated cells. Induction of p18 correlated with increased and sequential complex formation--first increasing association with CDK6 and then with CDK4 over the course of myogenic differentiation. All of the CDK6 and half of the CDK4 were complexed with p18 in terminally differentiated C2C12 cells as well as in adult mouse muscle tissue. Finally, kinase activity of CDK2 and CDK4 decreases as C2C12 cells differentiate, whereas the CDK6 kinase activity is low in both proliferating myoblasts and differentiated myotubes. Our results indicate that p18 may play a critical role in causing and/or maintaining permanent cell cycle arrest associated with mature muscle formation.
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PMID:Induction of p18INK4c and its predominant association with CDK4 and CDK6 during myogenic differentiation. 889 64

The cross-linking of surface immunoglobulins (sIg) of B cells can transmit a negative signal, resulting in cell cycle arrest, apoptosis or both. Signaling via the B cell antigen CD40 reverses the sIg-mediated negative signaling and induces activation and proliferation of B cells. We investigated the molecular mechanism for cell cycle regulation by negative and positive signaling via sIg and CD40, respectively, by using the B cell line WEHI-231. Cross-linking of sIg almost completely reduced the activity of cyclin-dependent kinase (Cdk) 2, essential for cell cycle progression in the late G1 phase, although the level of Cdk2 was not reduced. Among the factors that regulate Cdk2 activation, the activity of the Cdk-activating kinase (CAK) appeared intact and cyclin E was reduced only partially in sIg-cross-linked WEHI-231. In contrast, sIg cross-linking induced a significant Cdk inhibitor (CKI) activity. Since a 27-kDa protein was co-precipitated with Cdk2 in anti-Ig-treated, but not untreated WEHI-231, and the CKI activity in anti-Ig-treated WEHI-231 was neutralized by anti-p27Kip1 antibodies, it is most likely that p27Kip1 is responsible for the CKI activity induced by sIg cross-linking. p27Kip1 may thus play a role in growth inhibition of B cells by negative signaling via sIg. In contrast, CD40 signaling enhanced Cdk2 activity and reduced the p27Kip1 level in anti-Ig-treated WEHI-231, suggesting that the reduction of p27Kip1 plays an important role in the abrogation of sIg-mediated growth arrest by CD40 signaling. Taken together, p27Kip1 is likely to be a crucial target molecule of the negative signaling via sIg and the positive signaling via CD40 essential for T cell-dependent immune responses.
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PMID:Differential modulation of cyclin-dependent kinase inhibitor p27Kip1 by negative signaling via the antigen receptor of B cells and positive signaling via CD40. 889 56

Angiotensin II (Ang II) induces hypertrophy of cultured proximal tubular epithelial cells including the LLC-PK1 cell line. We have previously shown that this hypertrophy appears in the G1-phase of the cell cycle. Since progression through the cell cycle is controlled by a series of cyclin and cyclin-dependent kinase (CdK) complexes that may be inactivated by CdK inhibitors, we studied the expression of the CdK-inhibitor p27Kip1 in LLC-PK1 cells challenged with Ang II. Compared to cells grown in serum-free medium, Ang II treatment enhanced p27Kip1 protein, but not mRNA expression. This p27Kip1 induction was mediated through AT1-receptors. Exogenous TGF-beta also stimulated p27Kip1 protein expression. Immunoprecipitation experiments revealed that p27Kip1 preferentially associated with CdK4 in Ang II-treated LLC-PK1 cells and that the activity of this kinase was inhibited after Ang II-treatment, an effect that may be generated by increased p27Kip1 binding to cyclin D1-CdK4 complexes. In contrast, p27Kip1 was not associated with cyclin E-CdK2 complexes in Ang II-stimulated cells. Treatment of LLC-PK1 cells with p27Kip1 antisense, but not missense, oligonucleotides abolished the Ang II-mediated cell hypertrophy as measured by de novo protein synthesis and total protein content, and facilitated entry into the S-phase of the cell cycle. Our findings suggest that Ang II stimulates p27Kip1 expression in renal cells. Furthermore, this induction of the CdK-inhibitor appears pivotal in the hypertrophy induced by Ang II and elucidates the molecular mechanisms associated with this growth response in proximal tubular cells.
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PMID:Angiotensin II-stimulated hypertrophy of LLC-PK1 cells depends on the induction of the cyclin-dependent kinase inhibitor p27Kip1. 894 98

The cyclin-dependent kinase inhibitor p27Kip1 plays an important role in regulating cell-cycle progression. p27Kip1 directly inhibits the catalytic activity of cyclin/cdks (cyclin-dependent kinase) complexes and/or interferes physically with cyclin/cdks activation by CAK. Interestingly, the expression level of p27Kip1 mRNA was maximal in resting Go T-cells and rapidly declined following anti-CD3 activation. We report here the cloning of p27Kip1 gene from murine genomic DNA and the functional analysis of the promoter of the p27Kip1 gene. The gene consists of at least three exons and spans more than 5.6 kb of DNA. Primer extension and nuclease S1 protection analysis revealed two major transcription initiation sites. The promoter region lacked a TATA box but contained potential binding sites for the transcriptional factors including two Sp1, CRE, Myb and NFkB located at positions -153, -178, -286, -875, and -1011, respectively. To analyze the regulatory mechanisms controlling p27Kip1 gene expression, we characterized the 5'-flanking region from nt -1609 to +178. The -326 to -615 region contained positive regulatory elements.
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PMID:Characterization of the murine cyclin-dependent kinase inhibitor gene p27Kip1. 897 54

We show here that c-Myc antagonizes the cyclin-dependent kinase (CDK) inhibitor p27Kip1. p27 expressed from recombinant retroviruses in Rat1 cells associated with and inhibited cyclin E/CDK2 complexes, induced accumulation of the pRb and p130 proteins in their hypophosphorylated forms, and arrested cells in G1. Prior expression of c-Myc prevented inactivation of cyclin E/CDK2 as well as dephosphorylation of pRb and p130, and allowed continuous cell proliferation in the presence of p27. This effect did not require ubiquitin-mediated degradation of p27. Myc altered neither the susceptibility of cyclin E/CDK2 to inhibition by p27, nor the intrinsic CDK-inhibitory activity of p27, but induced sequestration of p27 in a form unable to bind cyclin E/CDK2. Neither Myc itself nor other G1-cyclin/CDK complexes were directly responsible for p27 sequestration. Retroviral expression of G1 cyclins (D1-3, E or A) or of the Cdc25A phosphatase did not overcome p27-induced arrest. Growth rescue by Myc required dimerization with Max, DNA binding and an intact transcriptional activation domain, as previously shown for cellular transformation. We propose that this activity is mediated by the product of an as yet unknown Myc-Max target gene(s) and represents an essential aspect of Myc's mitogenic and oncogenic functions.
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PMID:Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. 897 86

Breast cancer is the second leading cause of cancer death in North American women. There is considerable need for reliable prognostic markers to assist clinicians in making management decisions. Although a variety of factors have been tested, only tumor stage, grade, size, hormone receptor status, and S-phase fraction are used on a routine basis. The cell cycle is governed by a family of cyclin-dependent kinases (cdks), which are regulated by associated cyclins and by phosphorylation. p27Kip1, a cyclin-dependent kinase inhibitor, regulates progression from G1 into S phase by binding and inhibiting cyclin/cdks. p27Kip1 protein levels and/or activity are upregulated by growth inhibitory cytokines including transforming growth factor-beta (TGF-beta) and, thus, provide an important link between extracellular regulators and the cell cycle. Loss of p27Kip1, a negative cell-cycle regulator, may contribute to oncogenesis and tumor progression. However, p27Kip1 mutations in human tumors are extremely rare. We have demonstrated by immunohistochemistry that p27Kip1 protein levels are reduced in primary breast cancers and that this is associated with tumor progression in both in situ and invasive lesions. This was confirmed by western analysis, reflected in increased G1/S-phase cyclin-dependent kinase activities and shown to be regulated posttranscriptionally by in situ hybridization. Furthermore, on multivariate analysis, low p27Kip1 is a predictor of reduced disease-free survival. This simple and reliable immunohistochemical assay may become a routine part of breast cancer evaluation and may influence patient management.
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PMID:Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. 901 30

The effects of transforming growth factor beta (TGF-beta) were studied in closely related human mammary epithelial cells (HMEC), both finite-life-span 184 cells and immortal derivatives, 184A1S, and 184A1L5R, which differ in their cell cycle responses to TGF-beta but express type I and type II TGF-beta receptors and retain TGF-beta induction of extracellular matrix. The arrest-resistant phenotype was not due to loss of cyclin-dependent kinase (cdk) inhibitors. TGF-beta was shown to regulate p15INK4B expression at at least two levels: mRNA accumulation and protein stability. In TGF-beta-arrested HMEC, there was not only an increase in p15 mRNA but also a major increase in p5INK4B protein stability. As cdk4- and cdk6-associated p15INK4B increased during TGF-beta arrest of sensitive cells, there was a loss of cyclin D1, p21Cip1, and p27Kip1 from these kinase complexes, and cyclin E-cdk2-associated p27Kip1 increased. In HMEC, p15INK4B complexes did not contain detectable cyclin. p15INK4B from both sensitive and resistant cells could displace in vitro cyclin D1, p21Cip1, and p27Kip1 from cdk4 isolated from sensitive cells. Cyclin D1 could not be displaced from cdk4 in the resistant 184A1L5R cell lysates. Thus, in TGF-beta arrest, p15INK4B may displace already associated cyclin D1 from cdks and prevent new cyclin D1-cdk complexes from forming. Furthermore, p27Kip1 binding shifts from cdk4 to cyclin E-cdk2 during TGF-beta-mediated arrest. The importance of posttranslational regulation of p15INK4B by TGF-beta is underlined by the observation that in TGF-beta-resistant 184A1L5R, although the p15 transcript increased, p15INK4B protein was not stabilized and did not accumulate, and cyclin D1-cdk association and kinase activation were not inhibited.
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PMID:Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells. 911 14


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