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)

Mutations that lead to anchorage-independent survival are a hallmark of tumor cells. Adhesion of integrin receptors to extracellular matrix activates a survival signaling pathway in epithelial cells where Akt phosphorylates and blocks the activity of proapoptotic proteins such as the BCL2 family member Bad, the forkhead transcription factor FKHRL-1, and caspase 9. Insulin-like growth factor 1 (IGF-1) is a well-established epithelial cell survival factor that also triggers activation of Akt and can maintain Akt activity after cells lose matrix contact. It is not until IGF-1 expression diminishes (~16 h after loss of matrix contact) that epithelial cells deprived of matrix contact undergo apoptosis. This suggests that IGF-1 expression is linked to cell adhesion and that it is the loss of IGF-1 which dictates the onset of apoptosis after cells lose matrix contact. Here, we examine the linkage between cell adhesion and IGF-1 expression. While IGF-1 is able to maintain Akt activity and phosphorylation of proapoptotic proteins in cells that have lost matrix contact, Akt is not able to phosphorylate and inactivate another of its substrates, glycogen synthase kinase 3beta (GSK-3beta), under these conditions. The reason for this appears to be a rapid translocation of active Akt away from GSK-3beta when cells lose matrix contact. One target of GSK-3beta is cyclin D, which is turned over in response to this phosphorylation. Therefore, cyclin D is rapidly lost when cells are deprived of matrix contact, leading to a loss of cyclin-dependent kinase 4 activity and accumulation of hypophosphorylated, active Rb. This facilitates assembly of a repressor complex containing histone deacetylase (HDAC), Rb, and E2F that blocks transcription of the gene for IGF-1, leading to loss of Akt activity, accumulation of active proapoptotic proteins, and apoptosis. This feedback loop containing GSK-3beta, cyclin D, HDAC-Rb-E2F, and IGF-1 then determines how long Akt will remain active after cells lose matrix contact, and thus it serves to regulate the onset of apoptosis in such cells.
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PMID:Transcriptional repression by RB-E2F and regulation of anchorage-independent survival. 1131 58

Iron is essential for cellular proliferation in all organisms. When deprived of iron, the growth of cells is invariably inhibited. However, the mechanism involved remains largely unclear. In the present study, we have observed that subcytotoxic concentrations of desferroxamine mesylate (DFO), an iron chelator, specifically inhibited the transition from G1 to S-phase of Chang cells, a hepatocyte cell line. This was accompanied by the appearance of senescent biomarkers, such as enlarged and flattened cell morphology, senescence-associated beta-galactosidase activity and reduced expression of poly(ADP-ribose) polymerase. Concomitantly, p27Kip1 (where Kip is kinase-inhibitory protein) was induced markedly, whereas other negative cell-cycle regulators, such as p21Cip1 (where Cip is cyclin-dependent kinase-interacting protein), p15INK4B and p16INK4A (where INK is inhibitors of cyclin-dependent kinase 4), were not, implying its association in the G1 arrest. Furthermore, the induction of p27Kip1 was accompanied by an increased level of transforming growth factor beta1 (TGF-beta1) mRNA. When neutralized with an anti-(TGF-beta1) antibody, p27Kip1 induction was completely abolished, indicating that TGF-beta1 is the major inducer of p27Kip1. Finally, DFO-induced senescence-like arrest was found to be independent of p53, since cell-cycle arrest was still observed with two p53-negative cell lines, Huh7 and Hep3B cells. In conclusion, DFO induced senescence-like G1 arrest in hepatocyte cell lines and this was associated with the induction of p27Kip1 through TGF-beta1, but was independent of p53.
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PMID:Iron chelation-induced senescence-like growth arrest in hepatocyte cell lines: association of transforming growth factor beta1 (TGF-beta1)-mediated p27Kip1 expression. 1194 74

Cyclin D1 is downstream of erbB2 and is required for erbB2 transformation. Here we report thatcyclin D1 functions are essential, rate limiting for erbB2 transformation, and reciprocally increase erbB2 levels. This interaction depends on three cyclin D1 activities: cyclin-dependent kinase 4-dependent kinase activity, titration of p27, and an intrinsic transcriptional activity of cyclin D1. Drugs active against erbB2 and cyclin D1 (Herceptin and flavopiridol) were synergistically cytotoxic against erbB2-positive breast cancer cell lines. Addition of flavopiridol to Herceptin synergistically lowered erbB2 levels in these cells. Our data suggest the potential use of combinations of cyclin-dependent kinase inhibitors and Herceptin in breast cancer.
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PMID:Rate-limiting effects of Cyclin D1 in transformation by ErbB2 predicts synergy between herceptin and flavopiridol. 1195 82

Acyclic retinoid (ACR), a novel synthetic retinoid, can prevent the recurrence of human hepatoma after surgical resection of primary tumors, but the molecular mechanisms by which ACR exerts antitumor effects are not known. In this study, we found that ACR inhibited the growth of three human hepatoma cell lines. In HepG2 cells, this inhibition was associated with an arrest of the cell cycle in G(0)-G(1), increased cellular levels of p21(CIP1), decreased levels of the hyperphosphorylated form of the retinoblastoma protein, and decreased levels of cyclin D1, but no significant changes were seen in the levels of the p16(INK4a), p27(KIP1), cyclin-dependent kinase 4, cyclin-dependent kinase 6, glycogen synthase kinase 3beta, or beta-catenin proteins. ACR also caused a decrease in the level of cyclin D1 mRNA. Cotreatment of HepG2 human hepatoma cells with the proteasome inhibitor N-acetyl-Leu-Leu-norleu-al did not prevent the ACR-induced decrease in cyclin D1 protein, in contrast to the protective effect of N-acetyl-Leu-Leu-norleu-al on the cyclin D1 protein in cells treated with all-trans-retinoic acid. In transient transfection reporter assays, ACR, but not all-trans-retinoic acid, inhibited transcription from the cyclin D1 promoter. As reported previously in colon carcinoma cells, we found that in hepatoma cells, cyclin D1 promoter activity is markedly stimulated by the beta-catenin/T-cell factor pathway. Nevertheless, even in the presence of excess beta-catenin, ACR markedly inhibited the transcriptional activity of the cyclin D1 promoter. This is the first systematic study of the inhibitory effects of ACR, or any other retinoid compound, on beta-catenin/T-cell factor-stimulated cyclin D1 promoter activity in human tumor cells. These novel effects of ACR provide further evidence that ACR may be a valuable agent in the chemoprevention and therapy of hepatoma and possibly other human malignancies.
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PMID:Growth inhibition of human hepatoma cells by acyclic retinoid is associated with induction of p21(CIP1) and inhibition of expression of cyclin D1. 1212 33

Granulosa cell tumors (GCTs) of the ovary are relatively rare and account for <5% of all ovarian cancers. The molecular pathogenesis of these tumors is not well understood. We tested the hypothesis that cyclin-dependent kinase inhibitors, specifically the inhibitors of the cyclin-dependent kinase 4 (INK4) family, are targets for altered gene expression in GCTs. The status of RB1, INK4A, INK4B, INK4C, INK4D, and ARF in 13 adult and 2 juvenile ovarian GCTs was determined by reverse transcription-polymerase chain reaction of total RNA and exon-specific sequencing of genomic DNA. Tumors showing loss of INK4A expression were assayed further by exon-deletion analysis and methylation-specific PCR. None of the juvenile tumors demonstrated altered expression, but 7/12 (58%) adult GCTs lacked expression of INK4A, INK4B, or both. In one of these cases, we noted a homozygous deletion of the INK4A locus, and in the remaining tumors we found hypermethylation of the promoter region, a mechanism that can lead to gene inactivation. These data support a role for the INK4 family of CDK inhibitors in the biology of GCTs.
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PMID:Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors. 1220 82

BAG family proteins are regulatory co-chaperones for heat shock protein (Hsp) 70. Hsp70 facilitates the removal of injured proteins by ubiquitin-mediated proteasomal degradation. This process can be driven by geldanamycin, an irreversible blocker of Hsp90. We hypothesize that CAIR-1/BAG-3 inhibits Hsp-mediated proteasomal degradation. Human breast cancer cells were engineered to overexpress either full-length CAIR-1 (FL), which binds Hsp70, or a BAG domain-deletion mutant (dBAG) that cannot bind Hsp70. FL overexpression prevented geldanamycin-mediated loss of total and phospho-Akt and other Hsp client proteins. dBAG provided no protection, indicating a requirement for Hsp70 binding. Ubiquitinated Akt accumulated in FL-expressing cells, mimicking the effect of lactacystin proteasomal inhibition, indicating that CAIR-1 inhibits proteasomal degradation distal to protein ubiquitination in a BAG domain-dependent manner. Protein protection in FL cells was generalizable to downstream Akt targets, GSK3beta, P70S6 kinase, CREB, and other Hsp client proteins, including Raf-1, cyclin-dependent kinase 4, and epidermal growth factor receptor. These findings suggest that Hsp70 is a chaperone driving a multiprotein degradation complex and that the inhibitory co-chaperone CAIR-1 functions distal to client ubiquitination. Furthermore, poly-ubiquitination is not sufficient for efficient proteasomal targeting of Hsp client proteins.
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PMID:CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins. 1275 Mar 78

Death-associated protein kinase is a serine/threonine protein kinase implicated in promoting apoptosis and tumor suppression, whereas p16 is a tumor suppressor gene that inhibits cyclin-dependent kinase 4 and 6 activity and arrests the cell cycle in the G1 phase. Hypermethylation of death-associated protein kinase or p16 gene with resultant gene inactivation has been described in a wide variety of human cancers. Promoter methylation of the death-associated protein kinase and p16 gene has been found in about 55% and 30% cases of head and neck squamous cell carcinoma respectively but has not yet been analyzed in cutaneous premalignant and malignant lesions. A total of 33 cases were examined for evidence of death-associated protein kinase and p16 hypermethylation and these consist of 9 cases of spongiotic dermatitis as nonneoplastic skin control, 9 cases of actinic keratosis, 8 cases of squamous cell carcinoma in situ, and 7 cases of invasive squamous cell carcinoma. Death-associated protein kinase promoter methylation was detected in 1 case of squamous cell carcinoma in situ and 1 case of nonneoplastic skin control but none of the cases of invasive squamous cell carcinoma or actinic keratosis. P16 promoter methylation was detected in 1 case of invasive squamous cell carcinoma and 1 case of nonneoplastic skin control but none of the cases of squamous cell carcinoma in situ or actinic keratosis. Promoter hypermethylation of the death-associated protein kinase and p16 genes does not appear to play an important role in the development of cutaneous squamous cell carcinoma. The data thus suggest that the mechanisms of ultraviolet-induced cutaneous carcinomas differ from those involved in the development of head and neck squamous cell carcinoma, a malignant disease induced by tobacco and alcohol exposure.
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PMID:Analysis of promoter hypermethylation of death-associated protein kinase and p16 tumor suppressor genes in actinic keratoses and squamous cell carcinomas of the skin. 1286 Oct 61

Gankyrin is a 25-kDa hepatocellular carcinoma-associated protein that mediates protein-protein interactions in cell cycle control and protein degradation. It has been reported to form complexes with cyclin-dependent kinase 4, retinoblastoma protein, the S6b ATPase subunit of the 19 S regulator of the 26 S proteasome, and Mdm2, an E3 ubiquitin ligase involved in p53 degradation. It is the first protein described to bind both to the 26 S proteasome and to proteins in other complexes containing cyclin-dependent kinase(s) and p53 ubiquitylating activities, thus providing a mechanism for delivering cell cycle regulating machinery and ubiquitylated substrates to the proteasome for degradation. Gankyrin contains a 33-residue motif known as the ankyrin repeat that occurs five and a half to six times in the sequence. As a step toward understanding gankyrin interactions with its protein partners we have determined its three-dimensional crystal structure to 2.0-A resolution. It reveals that the entire 226-residue gankyrin polypeptide folds into seven ankyrin repeat elements. The ankyrin repeats, consisting of an antiparallel beta-hairpin followed by a perpendicularly oriented helix-loop-helix, pack side-by-side, creating an extended curved structure with a groove running across the long concave surface. Comparison with the structures of other ankyrin repeat proteins suggests that interactions with partner proteins are mediated by residues situated on this concave surface.
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PMID:The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53. 1457 99

Using a yeast interaction screen to search for proteins that interact with cyclin D3 in thyroid gland, we identified the cAMP-dependent AKAP95 (protein kinase A-anchoring protein 95). AKAP95 is a scaffolding protein that primarily co-fractionates with the nuclear matrix, whereas a minor fraction associates with chromatin in interphase cells. In co-transfected Chinese-hamster ovary cells, AKAP95 strongly interacted with the three D-type cyclins, but not with CDK4 (cyclin-dependent kinase 4) or with p27kip1. CDK4 displaced the interaction between cyclin D3 and AKAP95, suggesting that AKAP95 could not be the elusive bridging adaptor between D-type cyclins and CDK4 or play a role in the regulation of cyclin D3-CDK4 activity. Interaction between endogenous AKAP95 and cyclin D3 or cyclin D1 was detected in canine thyrocytes, human fibroblasts and NIH-3T3 cells. As both AKAP95 and cyclins D were recently reported to associate with minichromosome maintenance proteins [Eide, Tasken, Carlson, Williams, Jahnsen, Tasken and Collas (2003) J. Biol. Chem. 278, 26750-26756; Gladden and Diehl (2003) J. Biol. Chem. 278, 9754-9760], we hypothesize that the interaction between AKAP95 and D-type cyclins might serve to facilitate the emerging regulatory role of cyclin D-CDK4 in the formation of the prereplication complex at the DNA replication origins.
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PMID:A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95. 1464 Nov 7

Cyclin D-dependent kinases phosphorylate the retinoblastoma (Rb) protein and play a critical role in neuronal cell cycle control and apoptosis. Here we show that cyclin D1 became predominantly cytoplasmic as primary cortical progenitor cells underwent cell cycle withdrawal and terminal differentiation. Furthermore, ectopically expressed cyclin D1 sequestered in the cytoplasm of postmitotic neurons, whereas it efficiently entered the nucleus of proliferating progenitor cells. Cytoplasmic cyclin D1 were complexed with cyclin-dependent kinase 4 (CDK4), and also with CDK inhibitors, p27(Kip)(I) or p21(Cip)(I), which positively regulate assembly and nuclear accumulation of the cyclin D1-CDK4 complex. Although overexpression of p21(Cip)(I) promoted cyclin D1 nuclear localization, inhibition of either glycogen synthase kinase 3beta- or CRM1-mediated cyclin D1 nuclear export did not, suggesting that the inhibition of its nuclear import, rather than the acceleration of nuclear export, contributes to cytoplasmic sequestration of cyclin D1 in postmitotic neurons. In differentiated progenitor cells, nuclear localization of ectopic cyclin D1 induced apoptosis, and the DNA-damaging compound camptothecin caused nuclear accumulation of endogenous cyclin D1, accompanied by Rb phosphorylation. These results indicate that nuclear accumulation of cyclin D1 is inhibited in postmitotic neurons and suggest a role of its subcellular localization in neuronal death and survival.
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PMID:Role of cyclin D1 cytoplasmic sequestration in the survival of postmitotic neurons. 1464 67


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