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)

Deregulated expression of cyclin D1 is a feature of several neoplastic and proliferative disorders, but its normal role in the cell cycle remains unclear. Here we show that in a squamous carcinoma cell line with 11-fold amplification of the CCND1 gene, cyclin D1 associates specifically with p33cdk4 (PSK-J3) and p38cdk6 (PLSTIRE), two closely related members of the cyclin-dependent kinase (CDK) family. In these tumour cells, there is little evidence for an association between cyclin D1 and other CDKs, but in diploid human fibroblasts both CDK2 and CDK5 can be co-precipitated with cyclin D1, as well as CDK4. The data suggest that D-type cyclins participate in multiple interactions with CDKs but that the nature or stoichiometry of these associations may differ in different types of cell.
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PMID:CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1. 830 5

Estrogens are direct mitogens for hormone-responsive human breast cancercells, where they promote cell cycle progression and induce transcriptional activation of "immediate early" and cyclin genes. Nongenomic signaling by estrogens, including rapid changes of mitogen-activated protein(MAP) kinase and other signal-transduction-cascades activity, has been proposed to be essential for the mitogenic actions of these hormones and their nuclear receptors. Because regulation of gene transcription is considered a key step in cell cycle control by mitogenic protein kinase cascades, here we investigated the possibility that estrogen might induce the activation of extracellular signal-regulated kinase (Erk) 1/2-, c-Jun NH(2)-terminal kinase-, p38- or protein kinase A-responsive transcription factors in the cell nucleus during stimulation of early G(1) progression, a timing coincident with the maximum effects of these hormones on such enzyme activity. No significant changes in protein kinase-mediated transcription factor activity could be detected here after estrogen stimulation of either MCF-7 or ZR-75.1 cells. Furthermore, these steroids were able to induce activation of the human CCND1 gene promoter, accumulation of cyclin D1 and pRb phosphorylation, all key events in cell cycle stimulation by mitogens, even in the presence of Erk1/2 activation blockade by a MAP kinase-activating kinase (Mek)1/2 inhibitor. Thus, estrogens do not appear to convey significant protein kinase-dependent signaling to the cell nucleus during the early phases of human breast cancer cell stimulation. Furthermore, hormonal regulation of G(1) gene transcription can occur even without additional activation of the Mek-Erk1/2 pathway by estrogen receptors.
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PMID:Estrogens do not modify MAP kinase-dependent nuclear signaling during stimulation of early G(1) progression in human breast cancer cells. 1152 26

The retinoblastoma (RB)-Cyclin (CCN)D1-p16 cell cycle pathway has a crucial role in lung tumorigenesis. Impairment of the RB pathway has been shown to occur in almost all lung tumors. A deregulation at any level of this core RB pathway seems to make cells insensitive to the mitogenic signaling that is required for cell cycle progression. To date, almost all participants in this pathway have been shown to be altered to a various degree in lung tumors. Some of the alterations are mutually exclusive, including RB and p16INK4A . In small cell lung cancer, the RB tumor suppressor gene is inactivated in almost 90% of the tumors, whereas in non-small cell lung cancer, the cyclin-dependent kinase (CDK)4 inhibitor p16INK4A is inactivated in 40-60% of the tumors. Many mechanisms may be responsible for activating the RB-Cyclin D1 pathway, including activating (CDK4) and inactivating mutations (p16INK4A ), deletions (RB and p16INK4A ), amplifications (CCND1 and CDK4), silencing methylation (p16INK4A and RB), and hyper-phosphorylation (RB). As some of these alterations, such as p16INK4A methylation, can also be detected in bronchial lavage and serum, they could potentially serve as useful markers for the early detection of lung cancer. This review summarizes recent experiments describing the variable roles of key-player molecules of the RB pathway and different mechanisms by which the RB pathway can be altered in lung cancer.
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PMID:Regulation of the G1/S phase of the cell cycle and alterations in the RB pathway in human lung cancer. 1661 40

WNT signals are transduced to the canonical pathway for cell fate determination, and to the noncanonical pathway for control of cell movement and tissue polarity. Canonical WNT signals are transduced through Frizzled family receptors and LRP5/LRP6 coreceptor to the beta-catenin signaling cascade. Microtubule affinity-regulating kinase (PAR-1) family kinases, casein kinase I epsilon (CKI epsilon), and FRAT are positive regulators of the canonical WNT pathway, whereas APC, AXIN1, AXIN2, CKI alpha, NKD1, NKD2, beta TRCP1, beta TRCP2, ANKRD6, Nemo-like kinase (NLK), and peroxisome proliferator-activated receptor gamma (PPAR gamma) are negative regulators. Nuclear complex, consisting of T-cell factor/lymphoid enhancer factor, beta-catenin, BCL9/BCL9L, and PYGO, activates transcription of canonical WNT target genes such as FGF20, DKK1, WISP1, MYC, CCND1, and Glucagon (GCG). Noncanonical WNT signals are transduced through Frizzled family receptors and ROR2/RYK coreceptors to the Dishevelled-dependent (Rho family GTPases and c-jun NH(2)-terminal kinase) or the Ca(2+)-dependent (NLK and nuclear factor of activated T cells) signaling cascades. WNT signals are context-dependently transduced to both pathways based on the expression profile of WNT, SFRP, WIF, DKK, Frizzled receptors, coreceptors, and the activity of intracellular WNT signaling regulators. Epigenetic silencing and loss-of-function mutation of negative regulators of the canonical WNT pathway occur in a variety of human cancer. WNT, fibroblast growth factor (FGF), Notch, Hedgehog, and transforming growth factor beta/bone morphogenetic protein signaling network are implicated in the maintenance of tissue homeostasis by regulating self-renewal of normal stem cells as well as proliferation or differentiation of progenitor (transit-amplifying) cells. Breakage of the stem cell signaling network leads to carcinogenesis. Nonsteroidal anti-inflammatory drugs and PPAR gamma agonists with the potential to inhibit the canonical WNT signaling pathway are candidate agents for chemoprevention. ZTM000990 and PKF118-310 are lead compounds targeted to the canonical WNT signaling cascade. Anti-WNT1 and anti-WNT2 monoclonal antibodies show in vitro effects in cancer treatment. After the optimization, derivatives of small-molecule compound and human monoclonal antibody targeted to the WNT signaling pathway could be used in cancer medicine.
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PMID:WNT signaling pathway and stem cell signaling network. 1763 27

Using a large-scale case-control study, we examined whether common single-nucleotide polymorphisms (SNPs) within 13 genes involved in the cell cycle pathway are associated with breast cancer risk. Seventy-nine tag SNPs were used to evaluate 240 common SNPs found in the genes: CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKNIB, CDKN2A/CDKN2B, CDKN2C and CDKN2D. These were genotyped in 2270 cases and 2280 controls from the Studies in Epidemiology and Risks of Cancer Heredity (SEARCH) study. Tag SNPs showing evidence of statistically significant differences between cases and controls (P < 0.1) were genotyped in a further 2200 cases and 2280 controls from the same population. This approach found evidence for breast cancer-associated SNPs in four of the cell cycle genes: the cyclin CCNE1 rs997669 had an odds ratio (OR) (GG/AA) of 1.18 [95% confidence interval (95% CI) 1.04-1.34] P = 0.003 and the cyclin-dependent kinase inhibitors-CDKN1A rs3176336: OR (TT/AA) = 1.25 (95% CI 1.11-1.42) P = 0.0026; CDKN1B rs34330: OR (TT/CC) = 1.22 (95% CI 1.02-1.47) P = 0.013 and the region of CDKN2A/2B rs3731239: OR (CC/TT) = 0.90 (95% CI 0.79-1.03) P = 0.013 and rs3218005 OR (GG/AA) = 1.55 (95% CI 1.02-2.37) P = 0.013 (P-values unadjusted for multiple testing). We were able to exclude the D-type cyclins, cyclin-dependent kinases, CDKN2C and CDKN2D from having any significantly associated risk with breast cancer in our study population. The combined effects of the cell cycle genes considered here provide evidence for a significant association with breast cancer risk in a global test (P-heterogeneity = 0.010, P-trend = 0.048). Further large-scale studies are needed to confirm these results.
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PMID:Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. 1817 43

GLI family members are zinc-finger transcription factors, which are involved in embryogenesis and carcinogenesis through transcription regulation of GLI1, CCND1, CCND2, FOXA2, FOXC2, RUNX2, SFRP1, and JAG2. GLI1 transcription is upregulated in a variety of human tumors, such as basal cell carcinoma, lung cancer, breast cancer, gastric cancer, pancreatic cancer, and esophageal cancer. Hedgehog signaling via Smoothened cascade and receptor tyrosine kinase (RTK) signaling via PI3K-AKT cascade induce stabilization of GLI1 protein, whereas G-protein coupled receptor (GPCR) signaling via Gs-PKA cascade induces degradation of GLI1 protein. Here we report integrative genomic analyses of the GLI1 gene. The GLI1 and ARHGAP9 genes are located in a tail-to-tail manner with overlapping 3'-ends. ARHGAP9 was expressed in bone marrow, spleen, thymus, monocytes, and macrophages, whereas GLI1 was almost undetectable in normal tissues or cells with predominant ARHGAP9 expression. Because overlapping sense and anti-sense transcripts are annealed to each other to give rise to double-stranded RNAs functioning as endogenous RNAi, GLI1 expression might be negatively regulated by ARHGAP9 transcripts. GLI-binding element with one base substitution at the +1589-bp position from the transcriptional start site (TSS) of the human GLI1 gene was completely conserved in chimpanzee GLI1, mouse Gli1, and rat Gli1 genes. Ten Smad-binding elements, double E-boxes for EMT regulators, and double N-boxes for HES/HEY family members within intron 1 of the human GLI1 gene were also conserved in mammalian GLI1 orthologs. GLI1 transcription is upregulated due to Hedgehog, and TGFbeta signaling activation, whereas GLI1 transcription is downregulated due to Snail/Slug, and Notch signaling activation. Together these facts indicate that Hedgehog, TGFbeta, and RTK signals positively regulate GLI1, and that Notch, and GsPCR signals negatively regulate the GLI1.
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PMID:Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals. 1951 67

Hedgehog signaling is aberrantly activated in glioma, medulloblastoma, basal cell carcinoma, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, breast cancer, and other tumors. Hedgehog signals activate GLI family members via Smoothened. RTK signaling potentiates GLI activity through PI3K-AKT-mediated GSK3 inactivation or RAS-STIL1-mediated SUFU inactivation, while GPCR signaling to Gs represses GLI activity through adenylate cyclase-mediated PKA activation. GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin. Hedgehog signals are fine-tuned based on positive feedback loop via GLI1 and negative feedback loop via PTCH1, PTCH2, and HHIP1. Excessive positive feedback or collapsed negative feedback of Hedgehog signaling due to epigenetic or genetic alterations leads to carcinogenesis. Hedgehog signals induce cellular proliferation through upregulation of N-Myc, Cyclin D/E, and FOXM1. Hedgehog signals directly upregulate JAG2, indirectly upregulate mesenchymal BMP4 via FOXF1 or FOXL1, and also upregulate WNT2B and WNT5A. Hedgehog signals induce stem cell markers BMI1, LGR5, CD44 and CD133 based on cross-talk with WNT and/or other signals. Hedgehog signals upregulate BCL2 and CFLAR to promote cellular survival, SNAI1 (Snail), SNAI2 (Slug), ZEB1, ZEB2 (SIP1), TWIST2, and FOXC2 to promote epithelial-to-mesenchymal transition, and PTHLH (PTHrP) to promote osteolytic bone metastasis. KAAD-cyclopamine, Mu-SSKYQ-cyclopamine, IPI-269609, SANT1, SANT2, CUR61414 and HhAntag are small-molecule inhibitors targeted to Smoothened, GANT58, GANT61 to GLI1 and GLI2, and Robot-nikinin to SHH. Hedgehog signaling inhibitors should be used in combination with RTK inhibitors, GPCR modulators, and/or irradiation for cancer therapy.
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PMID:Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. 1986 Jun 66

Cell division cycle 7 is a widely expressed protein kinase implicated in cell division, cell cycle checkpoint mechanisms, and cancer progression. To determine the relationship of cell division cycle 7 protein expression with tumor phenotype, molecular features and prognosis, 2197 highly characterized breast carcinomas were analyzed on a tissue microarray. Detectable cell division cycle 7 expression was found in 1088 (57%) of breast cancer specimens and 228 (11.9%) exhibited a moderate or strong expression. High levels of cell division cycle 7 expression were significantly related to medullary histotype (P < .0001); high tumor grade (P < .0001); negative estrogen receptor status (P < .0001); high Ki67 expression level (P < .0001); p53 and p16 overexpression (P < .0001); and amplification of HER2 (P < .0001), c-myc (P < .0001), MDM2 (P = .043), CCND1 (P = .0084), and ESR1 (P = .0012) as well as with the number of amplified genes (P < .0001). There was also a tendency towards worse prognosis in cell division cycle 7 positive as compared to negative breast cancers. The relationship between cell division cycle 7 and number of amplifications was independent from tumor proliferation raising the possibility of a direct influence of cell division cycle 7 expression for amplification development. In conclusion, cell division cycle 7 is a replication associated protein with relationships to gene amplification and genomic instability in breast carcinomas. These data support the potential utility of newly developed small molecule cell division cycle 7 inhibitors as a therapeutic alternative in at least a subset of breast carcinomas.
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PMID:Overexpression of cell division cycle 7 homolog is associated with gene amplification frequency in breast cancer. 1989 97

Rhabdoid tumors (RT) are aggressive tumors characterized by genetic loss of SMARCB1 (SNF5, INI-1), a component of the SWI/SNF chromatin remodeling complex. No effective treatment is currently available. This study seeks to shed light on the SMARCB1-mediated pathogenesis of RT and to discover potential therapeutic targets. Global gene expression of 10 RT was compared with 12 cellular mesoblastic nephromas, 16 clear cell sarcomas of the kidney, and 15 Wilms tumors. In all, 114 top genes were differentially expressed in RT (P<0.001, fold change >2 or <0.5). Among these were downregulation of SMARCB1 and genes previously associated with SMARCB1 (ATP1B1, PTN, DOCK4, NQO1, PLOD1, PTP4A2, PTPRK); 28/114 top differentially expressed genes were involved with neural or neural crest development and were all sharply downregulated. This was confirmed by Gene Set Enrichment Analysis (GSEA). Neural and neural crest stem cell marker proteins SOX10, ID3, CD133, and Musashi were negative by immunohistochemistry, whereas Nestin was positive. Decreased expression of CDKN1A, CDKN1B, CDKN1C, CDKN2A, and CCND1 was identified, while MYC-C was upregulated. GSEA of independent gene sets associated with bivalent histone modification and polycomb group targets in embryonic stem cells showed significant negative enrichment in RT. Several differentially expressed genes were associated with tumor suppression, invasion, and metastasis, including SPP1 (osteopontin), COL18A1 (endostatin), PTPRK, and DOCK4. We conclude that RTs arise within early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin-dependent kinase inhibition, and trithorax/polycomb dysregulation.
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PMID:Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. 2021 51

The effect of prostaglandin (PG) on proliferation of chicken theca externa cells from prehierarchical small yellow follicles (SYF) was evaluated and involved signaling pathways as well as mRNA expression of cAMP response element binding protein (CREB1), cyclins (CCND1 and CCNE1) and cyclin-dependent kinases (CDKs) were investigated. Results showed that PGE(1) (1-100 ng/ml) manifested a similar proliferating effect as LH on theca externa cells, and this stimulating effect was restrained by the prostaglandin receptor antagonist SC19220 at 10(-7) to 10(-5)M. Moreover, prostaglandin synthase inhibitor indomethacin (10(-7) to 10(-5)M) suppressed LH-induced increase in the cell number. In addition, PGE(1)-stimulated cell proliferation was also predominantly hindered by H(89) (PKA inhibitor) instead of H(7) (PKC inhibitor). Meanwhile, BrdU incorporation experiment displayed similar changes with the cell number. Furthermore, H(89), SC19220 and indomethacin abolished the PGE(1)-stimulated increase in the expression of CREB1, CCND1/CDK6 and CCNE1/CDK2 mRNAs, indicating that cAMP/PKA/CREB1 signaling cascade was involved in PGE(1)-stimulated DNA synthesis. In conclusion, PG could promote proliferation of theca externa cells from prehierarchical follicles through changes in cyclin D1/CDK6, cyclin E1/CDK2 and CREB1 mRNA expression via cAMP/PKA and CREB1 signaling cascade. These results suggest that PG may promote development of chicken prehierarchical follicles and is related to dominant follicle selection in laying hens.
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PMID:Effect of prostaglandin on luteinizing hormone-stimulated proliferation of theca externa cells from chicken prehierarchical follicles. 2038 33


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