Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1alpha. A key question surrounding HIF-1alpha and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1alpha functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1alpha in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1alpha in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1alpha null growth plates, indicating defects in HIF-1alpha-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1alpha-dependent and -independent mechanisms. In particular, we provide evidence that VEGF expression is up-regulated in a HIF-1alpha-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1alpha in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1alpha response in vivo, and they provide new insights into mechanisms of growth plate development.
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PMID:Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. 1169 37

The aim of this study was to evaluate the expression profile of proteins involved in growing of human non-small cell lung cancer (NSCLC) in athymic nude mice. The expressions of 20 gene products in primary NSCLC of 170 patients were analyzed and the proteins were correlated with the transplantability of the carcinomas in nude mice. There was no relationship between xenotransplantability of human non-small cell lung cancer in nude mice and histology, stage or lymph node involvement. Of the analyzed proliferative factors PCNA, cyclin A, cyclin D, cdk2, cdk4 and cell cycle phases only cyclin D, cdk4 and the cell cycle phases were up-regulated in growing carcinomas. There was also a correlation between the apoptotic indices and the take rate in nude mice. Concerning microvessel density and angiogenic factors only VEGF showed a relation to xenotransplantability. Of the proto-oncogenes and suppressor gene products N-RAS, P53, FOS and JUN revealed a relationship to the take rate of NSCLC, while such a relationship was not found with MYC, ERBB-1 and ERBB-2. In a second step, a hierarchical cluster analysis was carried out. The resulting clusters were correlated with the take rate of the carcinomas in nude mice. The expression of JUN, N-RAS, FOS, cyclin D, and cdk4 were significantly different in both groups with non- overlapping confidence intervals. Thus, the up-regulation of the proteins JUN, N-RAS, FOS, cyclin D and cdk4 predicts the growth of NSCLC in nude mice.
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PMID:Expression profile of proteins involved in the xenotransplantability of non-small cell lung cancers into athymic nude mice. 1178 7

Human neuroblastoma (NB) tumors elaborate angiogenic peptides, and enhanced angiogenesis correlates with their aggressive behavior, metastatic spread and poor clinical outcome. Hence, inhibition of angiogenic factor production may represent a potential therapeutic target for NB treatment. There is currently little information regarding the stimuli that control NB production of angiogenic mediators. In this study, we analyzed the effects of hypoxia, a common feature of solid tumors and a major drive to tumor angiogenesis, and of PA, a tryptophan catabolite produced under inflammatory conditions and endowed with several biologic properties, on the production of the angiogenic activator VEGF by advanced-stage human NB cell lines. We demonstrate that both stimuli are potent inducers of VEGF expression and secretion. VEGF upregulation by PA involved iron chelation because iron sulfate prevented this effect whereas the iron-chelating agent DFX induced VEGF production. Conversely, the CDK inhibitor Flp completely blocked VEGF induction by hypoxia. This effect occurred as early as 3 hr after stimulation and did not require de novo protein synthesis. Moreover, Flp exerted similar inhibitory activity on VEGF induction by PA or DFX, suggesting that this compound targets an essential step in the signaling pathway that leads to VEGF expression. Our findings demonstrate that PA can modulate angiogenic factor production by tumor cells and establish the importance of Flp as an inhibitor of VEGF production by human NB.
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PMID:Flavopiridol inhibits vascular endothelial growth factor production induced by hypoxia or picolinic acid in human neuroblastoma. 1211 98

We have recently studied expression of estrogen receptors and the growth inhibitory effects of antiestrogens on human myeloma cells. In myeloma chemotherapy, Antiestrogens in combination with other chemotherapeutic agents, may have applications in which melphalan/predonisolone still remains the standard treatment. In this study, we examined expression of HER family molecules in myeloma cells to clarify the possible usage of anti-HER2-monoclonal antibody in the treatment of myeloma. Although the mRNA levels of HER family genes analyzed by RT-PCR were significantly lower in myeloma cells than breast cancer cells, some cell lines expressed a certain amount of HER2 and HER4 proteins. In addition, an anti-HER2 monoclonal antibody, rhumAbHER2, caused significant growth inhibition in six out of eight myeloma cell lines studied and these inhibitory effects were similar to those in the breast cancer cells studied previously. The rhumAbHER2 induced up-regulation of p21 family CDK-Is (cyclin dependent kinase inhibitors) and down-regulation of VEGF genes. Moreover, combination treatment with antiestrogen had an additive growth inhibitory effect. Such analyses may provide for use of rhumAbHER2 in myeloma treatment for the future.
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PMID:Expression of HER family receptors and effects of anti-HER2-antibody on human myeloma cell lines. 1296 96

Many malignant tumors including non-small cell lung cancer (NSCLC) express or over-express EGFR that have shown correlations with rapid growth, metastases, resistance to conventional chemotherapy or radiotherapy, and poor prognosis. Gefitinib is a potent and selective inhibitor of EGFR tyrosine kinase (EGFRTK). Gefitinib specifically inhibited EGF-stimulated cell proliferation in vitro and it also exhibited a broad anti-tumor spectrum against NSCLC, prostate, colorectal, and ovarian cancers in vivo. Gefitinib showed dose-dependent and reversible reduction of c-fos mRNA level and decreased Ki67 significantly in tumors in vivo. In in vitro studies, gefitinib arrested the cell cycle at G1 phase by inducing intrinsic cyclin-dependent kinase (cdk) inhibitors and following inhibition of cdk2. Apoptosis was also seen in gefitinib-treated tumor cells and skin biopsy samples from clinical study. Gefitinib inhibited VEGF production in tumor cells through inhibition of EGFR signaling, leading to suppression of angiogenesis. In clinical studies, gefitinib demonstrated therapeutic benefit in patients who failed conventional chemotherapy. No correlation has been established between the anti-tumor activity of gefitinib and EGFR expression level, whilst sensitivity factors to gefitinib are yet to be elucidated. Identification of sensitivity factors will be a key for effective use of EGFRTK inhibitors including gefitinib for cancer treatment.
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PMID:EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy. 1463 3

Increasing evidence suggests that neuronal apoptosis is triggered by the inappropriate activation of cyclin-dependent kinases leading to an abortive re-entry of neurons into the cell cycle. Pharmacological inhibitors of cell-cycle progression may therefore have value in the treatment of neurodegenerative diseases in humans. GW8510 is a 3' substituted indolone that was developed recently as an inhibitor of cyclin-dependent kinase 2 (CDK2). We found that GW8510 inhibits the death of cerebellar granule neurons caused by switching them from high potassium (HK) medium to low potassium (LK) medium. Although GW8510 inhibits CDK2 and other CDKs when tested in in vitro biochemical assays, when used on cultured neurons it only inhibits CDK5, a cytoplasmic CDK that is not associated with cell-cycle progression. Treatment of cultured HEK293T cells with GW8510 does not inhibit cell-cycle progression, consistent with its inability to inhibit mitotic CDKs in intact cells. Neuroprotection by GW8510 is independent of Akt and MEK-ERK signaling. Furthermore, GW8510 does not block the LK-induced activation of Gsk3beta and, while inhibiting c-jun phosphorylation, does not inhibit the increase in c-jun expression observed in apoptotic neurons. We also examined the effectiveness of other 3' substituted indolone compounds to protect against neuronal apoptosis. We found that like GW8510, the VEGF Receptor 2 Kinase Inhibitors [3-(1H-pyrrol-2-ylmethylene)-1,3-dihydroindol-2-one], {(Z)-3-[2,4-Dimethyl-3-(ethoxycarbonyl)pyrrol-5-yl)methylidenyl]indol-2-one} and [(Z)-5-Bromo-3-(4,5,6,6-tetrahydro-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one], the Src family kinase inhibitor SU6656 and a commercially available inactive structural analog of an RNA-dependent protein kinase inhibitor 5-Chloro-3-(3,5-dichloro-4-hydroxybenzylidene)-1,3-dihydro-indol-2-one, are all neuroprotective when tested on LK-treated neurons. Along with our recent identification of the c-Raf inhibitor GW5074 (also a 3' substituted indolone) as a neuroprotective compound, our findings identify the 3' substituted indolone as a core structure for the designing of neuroprotective drugs that may be used to treat neurodegenerative diseases in humans.
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PMID:Inhibition of neuronal apoptosis by the cyclin-dependent kinase inhibitor GW8510: identification of 3' substituted indolones as a scaffold for the development of neuroprotective drugs. 1583 13

Malignant pleural mesothelioma, although uncommon, is highly lethal. There is a high correlation between associated environmental exposure factors, carcinogens, and its development. Carcinogenesis is also mediated by genetic defects that result in loss of tumor suppressors or over expression of proto-oncogenes. Factors such as the loss of CDK inhibition function, IGF stimulatory pathways, p14(ARF), p15(INK4b), p16(INK4a), p21, and p53 loss or mutation, VEGF and COX over expression are discussed. Correlations to potential therapeutic modalities are made.
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PMID:Molecular pathways in malignant pleural mesothelioma. 1621 11

For many breast cancer patients, human chorionic gonadotropin beta (hCGbeta), which is a subunit of a hormone produced by the trophoblast and is essential for maintaining pregnancy, is expressed in the breast cancer cells. However, the mechanism as to how the CGbeta in cell affects the cancer development is not very clear. Mouse breast carcinoma 4T1 with stably hCGbeta expression (4T1-hCGbeta) was established and transplanted into the Balb/c mouse abdominal mammary gland. hCGbeta suppressed breast cancer cell viability in vitro, and dramatically inhibited tumor growth and attenuated tumor vessel formation in vivo. An 86-88% reduction in tumor volume in animals injected with breast cancer expressing hCGbeta, as opposed to those injected with breast cancer without hCGbeta expression, was observed. The production of p21 was promoted by hCGbeta, whereas the Cdk2 was decreasing. These indicate that p21 signal pathway is involved in this process. Significant apoptosis was also detected in hCGbeta-expressing breast cancer cells as well as the enhancement of Bax protein expression. Moreover, hCGbeta blocked the blood vessels formation by inhibiting the expression of MMP9 and VEGF. Further hormone secretion analyses show that the anti-tumor activity induced by hCGbeta is not related to the endocrine function.
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PMID:Apoptosis and tumor inhibition induced by human chorionic gonadotropin beta in mouse breast carcinoma. 1692 66

Chemoprevention represents a promising strategy to reducing the incidence of prostate cancer which afflicts more than 240,000 males annually in the U.S. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CCDO-Me) and C-28 imidazole (CDDO-Im) derivatives are synthetic oleanane triterpenoids that exhibit several-fold more potent antiinflammatory activity than naturally occurring oleanolic acid, but have not been investigated for prevention of the prostate. In order to evaluate the anticancer activity of CDDOs for prostate cancer, we have investigated the effect of synthetic oleanane triterpenoids on molecular targets relevant to the chemoprevention and treatment of prostate cancer in vitro in TRAMPC-1 cells derived from the primary tumor in the prostate of a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse. Data demonstrate that CDDOs strongly inhibit the proliferation of TRAMPC-1 cells with a potency order of CDDO-Me>CDDO-Im>CDDO. Because CDDO-Me showed the most growth inhibitory activity it was further analyzed for the anticancer activity. CDDO-Me induced apoptosis in TRAMPC-1 cells as shown by the increased binding of annexin V-FITC and cleavage of procaspases 3, -8, and -9. It effectively inhibited the molecular targets such as p-Akt, NF-kappaB, and p-mTOR and downstream effectors of mTOR (p-S6K1, cyclin-D1, and cdk4). Further, CDDO-Me inhibited NF-kappaB-regulated antiapoptotic Bcl-2, Bcl-xL, and XIAP and proangiogenic VEGF. Taken together, these data demonstrate that CDDO-Me is potentially a potent chemopreventive agent that inhibits several molecular targets that are known to play critical roles in the development and progression of prostate cancer.
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PMID:CDDO-Me inhibits proliferation, induces apoptosis, down-regulates Akt, mTOR, NF-kappaB and NF-kappaB-regulated antiapoptotic and proangiogenic proteins in TRAMP prostate cancer cells. 1847 40

Oral Cancer Overexpressed 1 (ORAOV1) is a novel gene locating at chromosome band 11q13. Recent studies have suggested its role as a candidate oncogene in oral squamous cell carcinoma (OSCC) and its prognostic value for patients with OSCC. Till now, the detailed function of ORAOV1 in OSCC has remained undefined. In this study, we have investigated the role of ORAOV1 in OSCC tumorigenesis by down-regulating its expression. Small interfering RNA (siRNA) has been applied to inhibit the expression of ORAOV1 in OSCC cells. We found that the OSCC cells with reduced ORAOV1 showed retarded cell growth in vitro and displayed inhibition in both tumor growth and tumor angiogenesis in vivo. Further analyses reveal that the retarded cell growth is associated with an increase in apoptosis involving the activation of caspase 3-dependent pathway and a cell cycle arrest at the S-phase with a downregulation of cyclin A, cyclin B1 and cdc2. The suppressed tumor growth in vivo may be attributed to synergistic effect between inhibition in cell growth and suppression of tumor angiogenesis. The latter is most likely because of a suppression of VEGF. Taken together, we demonstrate that ORAOV1 plays pivotal roles in the growth and angiogenesis of OSCC. Thus, ORAOV1 may be a novel target that could be explored to develop therapeutic strategy in OSCC management.
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PMID:Oral cancer overexpressed 1 (ORAOV1): a regulator for the cell growth and tumor angiogenesis in oral squamous cell carcinoma. 1868 49


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