Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of two families of seven distinct mammalian cyclin-dependent kinase (CDK) inhibitor genes is thought to mediate the complexity of connecting a variety of cellular processes to the cell cycle control pathway. The distinct pattern of tissue expression of CDK inhibitor genes suggests that they may function as tumor suppressors with different tissue specificities. To test this hypothesis, we have characterized two strains of double mutant mice lacking either p18(INK4c) and p27(KIP1) or p18(INK4c) and p21(CIP1/WAF1). Loss of both p18 and p27 function resulted in the spontaneous development by 3 months of age of at least eight different types of hyperplastic tissues and/or tumors in the pituitary, adrenals, thyroid, parathyroid, testes, pancreas, duodenum, and stomach. Six of these hyperplastic tissues and tumors were in endocrine organs, and several types of tumors routinely developed within the same animal, a phenotype reminiscent of that seen in combined human multiple endocrine neoplasia syndromes. The p18-p21 double null mice, on the other hand, developed pituitary adenomas, multifocal gastric neuroendocrine hyperplasia, and lung bronchioalveolar tumors later in life. G(1) CDK2 and CDK4 kinase activities were increased in both normal and neoplastic tissues derived from mice lacking individual CDK inhibitors and were synergistically stimulated by the simultaneous loss of two CDK inhibitors. This indicates that an increase in G(1) CDK kinase activity is a critical step during but is not sufficient for tumor growth. Our results suggest that functional collaborations between distinct CDK inhibitor genes are tissue specific and confer yet another level of regulation in cell growth control and tumor suppression.
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PMID:Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. 1091 96

Epidemiological evidence has suggested an association between diets rich in antioxidants and diminished risks of various types of cancer. Proposed mechanisms for protective effects of antioxidants have involved inhibition of free radical-mediated DNA damage. Recent data suggest that antioxidants may prevent or eliminate cancerous cells through their ability to inhibit proliferation or to induce programmed cell death (PCD). To begin to identify cell cycle and cell death regulatory factors involved in antioxidant-induced growth arrest and PCD, we have studied colorectal carcinoma cells (CRCs) that differ in expression of the tumor suppressor protein p53, and of the cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1). The antioxidants, N-acetylcysteine (NAC) and vitamin E either inhibited proliferation in a p53-independent manner without affecting cell viability or induced cell death. Growth arrest was not associated with upregulation of the CDK inhibitors p21(Waf1/Cip1), p18(ink4c) or p16(ink4a), but was associated with a decrease in reactive oxygen species (ROS). In contrast to previous observations, the absence of p21(Waf1/Cip1) increased susceptibility of CRCs to antioxidant-induced PCD. NAC decreased levels of retinoblastoma protein (Rb) phosphorylation in all cells tested, but Rb was cleaved only in cells which underwent NAC-induced death. Although NAC decreased ROS in all cells studied, cell lines in which PCD occurred had higher baseline levels of ROS than cell lines in which proliferation was blocked. These observations suggest that expression of p21(Waf1/Cip1) and basal levels of ROS are important determinants of outcome after antioxidant treatment.
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PMID:p53-independent inhibition of proliferation and p21(WAF1/Cip1)-modulated induction of cell death by the antioxidants N-acetylcysteine and vitamin E. 1093 2

Epidemiological, in vitro cell culture, and in vivo animal studies have shown that green tea or its constituent polyphenols, particularly its major polyphenol epigallocatechin-3-gallate (EGCG) may protect against many cancer types. In earlier studies, we showed that green tea polyphenol EGCG causes a G0/G1-phase cell cycle arrest and apoptosis of human epidermoid carcinoma (A431) cells. We also demonstrated that these effects of EGCG may be mediated through the inhibition of nuclear factor kappa B that has been associated with cell cycle regulation and cancer. In this study, employing A431 cells, we provide evidence for the involvement of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery during cell cycle deregulation by EGCG. As shown by immunoblot analysis, EGCG treatment of the cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, p16 and p18, (ii) downmodulation of the protein expression of cyclin D1, cdk4 and cdk6, but not of cyclin E and cdk2, (iii) inhibition of the kinase activities associated with cyclin E, cyclin D1, cdk2, cdk4 and cdk6. Taken together, our study suggests that EGCG causes an induction of G1-phase ckis, which inhibit the cyclin-cdk complexes operative in G0/G1 phase of the cell cycle thereby causing a G0/G1-phase arrest of the cell cycle, which is an irreversible process ultimately resulting in an apoptotic cell death. We suggest that the naturally occurring agents such as green tea polyphenols which may inhibit cell cycle progression could be developed as potent anticancer agents for the management of cancer.
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PMID:Cell cycle dysregulation by green tea polyphenol epigallocatechin-3-gallate. 1096 66

Hepatocytes undergo marked changes in proliferation during normal liver development. In order to elucidate the mechanism for these changes, we examined the ontogeny of expression for the known cyclin-dependent kinase inhibitors (CKIs), p15(Ink4b), p16(Ink4a), p18(Ink4c), p19(Ink4d), p21(Cip1), p27(Kip1) and p57(Kip2). All except p16(Ink4a) were expressed at some time between late gestation and adulthood. The mRNA and protein expression patterns for p15(Ink4b) and p57(Kip2) were consistent with a role for these CKIs in the regulation of hepatocyte proliferation. Specifically, p57(Kip2) may contribute to hepatocyte growth arrest that occurs in term fetuses, while p15(Ink4b) may contribute to the maintenance of adult hepatocytes in a quiescent state. These results assign a possible role to two CKIs not previously identified as involved in hepatocyte cell cycle control.
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PMID:A potential role for p15(Ink4b) and p57(Kip2) in liver development. 1104 73

Development of skeletal cartilage is characterized with coupling growth arrest and cell differentiation. Here, to understand the cyclin-dependent kinase inhibitors involved in the progression of chondrogenic differentiation, we examined changes in the expression levels of cyclin-dependent kinase inhibitor members using mouse ATDC5 prechondrocytes as a widely used in vitro model of cartilage differentiation. Up-regulation of p21 and p27 mRNA was observed following a decrease in growth rate of prechondrocytes, and both transcripts subsequently accumulated during chondrogenic differentiation; p15, p18, and p19 mRNA, in contrast, did not change during differentiation. Only the up-regulation of p21 mRNA during differentiation was prevented by the continuous treatment of early chondrogenic inhibitor, parathyroid hormone, indicating a close correlation between differentiation and p21 induction in ATDC5 cells. Therefore, to examine the role of p21 during chondrogenesis, we established stable cell lines overexpressing full-length p21 antisense RNA in ATDC5. The reduction of endogenous p21 in these cell lines caused inhibition of early chondrogenic differentiation in ATDC5, indicating that p21 gene plays an important role in this process of the cells in vitro. Furthermore, the level of p21 protein and p21.CDK2 complexes transiently increased during differentiation, but not in undifferentiated cells, leading to a decrease in CDK2-associated kinase. However, differentiation-dependent expressed p21 protein was degraded by a proteasome-dependent pathway. Thus, the progression of chondrogenic differentiation requires down-regulation of CDK2-associated kinase with an increase in p21 protein and subsequent degradation of this protein by a proteasomal pathway.
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PMID:p21Cip-1/SDI-1/WAF-1 gene is involved in chondrogenic differentiation of ATDC5 cells in vitro. 1140 16

The inhibitors of cyclin-dependent kinase (CDK) 4 (INK4) bind CDK4/6 to prevent their association with D-cyclins and G(1) cell cycle initiation and progression. We report here that among the seven CDK inhibitors, p18(INK4c) played an important role in modulating TCR-mediated T cell proliferation. Loss of p18(INK4c) in T cells led to hyperproliferation in response to CD3 stimulation. p18(INK4c)-null mice developed lymphoproliferative disorder and T cell lymphomas. Expression of IL-2, IL-2R-alpha, and the major G(1) cell cycle regulatory proteins was not altered in p18-null T cells. Both FK506 and rapamycin efficiently inhibited proliferation of p18-null T cells. In activated T cells, p18(INK4c) remained constant, and preferentially associated with and inhibited CDK6 but not CDK4. We propose that p18(INK4c) sets an inhibitory threshold in T cells and one function of CD28 costimulation is to counteract the p18(INK4c) inhibitory activity on CDK6-cyclin D complexes. The p18(INK4c) protein may provide a novel target to modulate T cell immunity.
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PMID:An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation. 1154 16

Most spontaneously developing hyperplastic and neoplastic lesions of the pituitary occur in the anterior pituitary. Targeted disruption of various cell-cycle proteins, including Rb, p27(kip1) (p27), and p18(INK4c) (p18), is associated with intermediate lobe pituitary hyperplasia. To develop a model of anterior pituitary proliferation to study the pathogenesis of pituitary tumors, we crossed the glycoprotein hormone alpha-subunit (alphaSU)-null mice that develop thyroid-stimulating hormone (TSH) cell hyperplasia with p18-null mice. The resulting offsprings developed accelerated enlargement of the anterior lobe with predominantly TSH cell hyperplasia. Immunohistochemical and histological analyses of these mice along with p27/p18 double-null mice, p18-null mice, and p27-null mice showed evidence of TSH, adrenocorticotropic hormone, prolactin, and luteinizing hormone hyperplasia. To determine whether there were alterations of p27 and the target proteins implicated in the ubiquitin degradation of p27 and other cyclin-dependent kinase inhibitors, we examined expression of SKP 2, Grb 2, and Jab 1 in the pituitaries of null mice. In the alphaSU-null mice there were decreased levels of SKP 2 and elevated levels of Grb 2 expression by Western blot analysis. Immunohistochemical analysis of the pituitary showed elevated Grb 2 in alphaSU-null and p18/alphaSU double-null mice. Jab 1 levels were not different from controls in the pituitary. These results show that 1) the p18/alphaSU double-null mice represent a good model to study the rapid development of anterior pituitary hyperplasia, and 2) various proteins important in p27 and other cyclin-dependent kinase inhibitor protein degradation are altered in the pituitary of alphaSU-null and p18/alphaSU double-null mouse models.
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PMID:Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation. 1189 Dec 12

Adult T cell leukemia/lymphoma (ATLL) is one of the peripheral T cell malignant neoplasms strongly associated with human T cell leukemia virus type-I (HTLV-I). Although the viral transactivating protein Tax has been proposed to play a critical role in leukemogeneis as shown by its transforming activity in various experimental systems, additional cellular events are required for the development of ATLL. One of the genetic events in ATLL is inactivation of tumor suppressor genes. Among many candidates for tumor suppressor genes, the main genetic events have been reported to center around the cyclin-dependent kinase inhibitors ((CDKIs) p15INK4A, p16INK4B, p18INK4C, p19INK4D, p21WAF1, p27KIP1, and p57KIP2), p53 and Rb genes; all of them play a major regulatory role during G1 to S transition in the cell cycle. Acute/lymphomatous ATLL has frequent alterations of p15 (20%) and p16 (28-67%), while chronic/smoldering ATLL has fewer abnormalities of p15 (0-13%) and p16 (5-26%). Most of these changes are deletion of the genes; fewer samples have mutations. ATLL patients with deleted p15 and/or p16 genes have significantly shorter survival than those individuals with both genes preserved. Although genetic alterations of p18, p19, p21, p27 have rarely been reported, inactivation of these genes may contribute to the development of ATLL because low expression levels of these genes seem to mark ATLL. The p53 gene is mutated in 10-50% of acute/lymphomatous ATLL. Functional impairment of the p53 protein, even if the gene has wild-type sequences, has been suggested in HTLV-I infected cells. Each of these genetic events are mainly found in acute/lymphomatous ATLL, suggesting that alterations of these genes may be associated with transformation to an aggressive phenotype. The Rb tumor suppressor gene is infrequently structurally altered, but one half of ATLL cases have lost expression of this key protein. Notably, alterations of one of the CDKIs, p53 and Rb genes appear to obviate the need for inactivation of other genes in the same pathway. A novel tumor suppressor gene on chromosome 6q may also have a critical role in the pathogenesis of ATLL. Taken together, tumor suppressor genes are frequently altered in acute/lymphomatous ATLL and their alteration is probably the driving force fueling the transition from chronic/smoldering to acute/lymphomatous ATLL.
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PMID:Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL). 1204 Apr 38

B cell terminal differentiation is associated with the onset of high-level antibody secretion and cell cycle arrest. Here the cyclin-dependent kinase (CDK) inhibitor p18(INK4c) is shown to be required within B cells for both terminating cell proliferation and differentiation of functional plasma cells. In its absence, B cells hyperproliferate in germinal centers and extrafollicular foci in response to T-dependent antigens but serum antibody titers are severely reduced, despite unimpaired germinal center formation, class switch recombination, variable region-directed hypermutation, and differentiation to antibody-containing plasmacytoid cells. The novel link between cell cycle control and plasma cell differentiation may, at least in part, relate to p18(INK4c) inhibition of CDK6. Cell cycle arrest mediated by p18(INK4C) is therefore requisite for the generation of functional plasma cells.
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PMID:CDK inhibitor p18(INK4c) is required for the generation of functional plasma cells. 1219 89

To address the role of N-myc in neurogenesis and in nervous system tumors, it was conditionally disrupted in neuronal progenitor cells (NPCs) with a nestin-Cre transgene. Null mice display ataxia, behavioral abnormalities, and tremors that correlate with a twofold decrease in brain mass that disproportionately affects the cerebellum (sixfold reduced in mass) and the cerebral cortex, both of which show signs of disorganization. In control mice at E12.5, we observe a domain of high N-Myc protein expression in the rapidly proliferating cerebellar primordium. Targeted deletion of N-myc results in severely compromised proliferation as shown by a striking decrease in S phase and mitotic cells as well as in cells expressing the Myc target gene cyclin D2, whereas apoptosis is unaffected. Null progenitor cells also have comparatively high levels of the cdk inhibitors p27(Kip1) and p18(Ink4c), whereas p15(Ink4b), p21(Cip1), and p19(Ink4d) levels are unaffected. Many null progenitors also exhibit altered nuclear morphology and size. In addition, loss of N-myc disrupts neuronal differentiation as evidenced by ectopic staining of the neuron specific marker betaTUBIII in the cerebrum. Furthermore, in progenitor cell cultures derived from null embryonic brain, we observe a dramatic increase in neuronal differentiation compared with controls. Thus, N-myc is essential for normal neurogenesis, regulating NPC proliferation, differentiation, and nuclear size. Its effects on proliferation and differentiation appear due, at least in part, to down-regulation of a specific subset of cyclin-dependent kinase inhibitors.
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PMID:N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. 1238 68


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