Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied gene amplification of genes located in 1q32 (GAC1, ELF3, MDM4, and ren1), 4q11 (PDGFR-alpha), and in 12q13-14 (MDM2 and CDK4) using quantitative real-time PCR in a group of 86 tumors consisting of 44 WHO grade IV glioblastomas (GBM) (34 primary and 10 secondary tumors), 21 WHO grade III anaplastic astrocytomas (AA), and 21 WHO grade II astrocytomas (AII). Gene amplification was present in 56 of the 86 samples (65%) in at least 1 gene in our series. GAC1 (51%) and MDM4 (27%) were the most frequently amplified genes within the 1q32 amplicon, and their higher amplification frequency was statistically significant (P<0.05, chi) in the low-grade astrocytomas. Concordant co-amplification was determined for ELF3 and ren1 or ren1 and MDM4 in the grade III-IV tumors. MDM2 amplification was significantly more frequent in primary GBM (16%) than was in secondary GBM (0%). The present study shows that gene amplification in the studied regions is already present in low-grade astrocytic tumors and that amplification of some genes may represent another molecular marker to differentiate primary from secondary GBM.
Diagn Mol Pathol 2005 Dec
PMID:Real-time quantitative PCR analysis of regions involved in gene amplification reveals gene overdose in low-grade astrocytic gliomas. 1631 92

Valproic acid is a well-tolerated anticonvulsant that has been identified recently as a histone deacetylase inhibitor. To evaluate the antitumor efficacy and mechanisms of action of valproic acid in medulloblastoma and supratentorial primitive neuroectodermal tumor (sPNET), which are among the most common malignant brain tumors in children with poor prognosis, two medulloblastoma (DAOY and D283-MED) and one sPNET (PFSK) cell lines were treated with valproic acid and evaluated with a panel of in vitro and in vivo assays. Our results showed that valproic acid, at clinically safe concentrations (0.6 and 1 mmol/L), induced potent growth inhibition, cell cycle arrest, apoptosis, senescence, and differentiation and suppressed colony-forming efficiency and tumorigenicity in a time- and dose-dependent manner. The medulloblastoma cell lines were more responsive than the sPNET cell line and can be induced to irreversible suppression of proliferation and significantly reduced tumorigenicity by 0.6 and 1 mmol/L valproic acid. Daily i.p. injection of valproic acid (400 mg/kg) for 28 days significantly inhibited the in vivo growth of DAOY and D283-MED s.c. xenografts in severe combined immunodeficient mice. With Western hybridization and real-time reverse transcription-PCR, we further showed that the antitumor activities of valproic acid correlated with induction of histone (H3 and H4) hyperacetylation, activation of p21, and suppression of TP53, CDK4, and CMYC expression. In conclusion, valproic acid possesses potent in vitro and in vivo antimedulloblastoma activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, valproic acid may represent a novel therapeutic option in medulloblastoma treatment.
Mol Cancer Ther 2005 Dec
PMID:Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. 1637 6

The C/EBPalpha transcription factor regulates growth and differentiation of several tissues during embryonic development. Several hypotheses as to how C/EBPalpha inhibits cellular growth in vivo have been derived, mainly from studies of tissue culture cells. In fetal liver it has been proposed that a short, centrally located, 15-amino-acid proline-histidine-rich region (PHR) of C/EBPalpha is responsible for the growth-inhibitory function of the protein through its ability to interact with CDK2 and CDK4, thereby inhibiting their activities. Homozygous Cebpa(DeltaPHR/DeltaPHR) (DeltaPHR) mice, carrying a modified cebpa allele lacking amino acids 180 to 194, were born at the Mendelian ratio, reached adulthood, and displayed no apparent adverse phenotypes. When fetal livers from the DeltaPHR mice were analyzed for their expression of cell cycle markers, bromodeoxyuridine incorporation, cyclin-dependent kinase 2 kinase activity, and global gene expression, we failed to detect any cell cycle or developmental differences between the DeltaPHR mice and their control littermates. These in vivo data demonstrate that any C/EBPalpha-mediated growth repression via the PHR as well as the basic region is dispensable for proper embryonic development of, and cell cycle control in, the liver. Surprisingly, control experiments performed in C/EBPalpha null fetal livers yielded similar results.
Mol Cell Biol 2006 Feb
PMID:The proline-histidine-rich CDK2/CDK4 interaction region of C/EBPalpha is dispensable for C/EBPalpha-mediated growth regulation in vivo. 1642 55

Previous results of our cDNA microarray analysis to look for genes whose expression level correlates well with in vitro tubulogenesis by NP31 endothelial cells revealed the transcription factor ATF3 known to be responsive to stress such as reactive oxygen species (ROS). Anti-ATF3 small interfering RNA gave an inhibitory influence on tube formation by NP31 cells expressing an activated form of the vascular endothelial growth factor receptor 1 (VEGFR-1) kinase. When expression of ATF3 was regulated under the control of tetracycline system in NP31 cells, they acquired the tubulogenic ability upon ATF3 induction. While ATF3 failed to induce expressions of VEGF and VEGFR, it regulated those of CDK2, CDK4, p8, plasminogen activator inhibitor 1, integrin alpha1, subunit and matrix metalloprotease MMP13. In H2O2-stimulated NP31 cells as well as endothelial cells of glomerulus and aorta of Otsuka-Long-Evans-Tokushima-Fatty diabetic model rats, concomitantly enhanced expressions of ATF3, PAI-1, and p8 were observed. Given the proposed hypothesis of the close linkage between diabetic angiopathy and ROS, those data suggest that ROS-associated diabetic complication may involve ATF3-mediated pathological angiogenesis.
Mol Cell Biol 2006 Feb
PMID:Oxidative stress-responsive transcription factor ATF3 potentially mediates diabetic angiopathy. 1642 60

The tight junction protein ZO-1 inhibits G1/S-phase transition by cytoplasmic sequestration of a complex formed by CDK4 and the transcription factor ZONAB. Canine ZONAB is the homologue of human DbpA, an E2F target gene that is overexpressed in different carcinomas. Since the ZONAB target genes that are involved in G1/S-phase transition are unknown, we employed the mammary epithelial cell line MCF-10A and cDNA arrays to screen for such genes. We identified genes encoding cell cycle and replication proteins whose expression was altered due to increased ZONAB expression. For proliferative cell nuclear antigen and cyclin D1 genes, we show that increased mRNA levels resulted in increased protein levels and we identified ZONAB-responsive elements in their promoters by using different approaches, including chromatin immunoprecipitation assays. RNA interference and overexpression of ZONAB affected the proliferation of both MCF-10A and MDCK cells as well as the differentiation of MDCK cells into polarized cysts in three-dimensional cultures. These results indicate that ZONAB regulates the transcription of genes that are important for G1/S-phase progression and links tight junctions to the transcriptional control of key cell cycle regulators and epithelial cell differentiation.
Mol Cell Biol 2006 Mar
PMID:Regulation of PCNA and cyclin D1 expression and epithelial morphogenesis by the ZO-1-regulated transcription factor ZONAB/DbpA. 1650 13

ZD1839 ("Iressa") is an orally active, selective epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor. We evaluated the antitumor activity of ZD1839 in combination with HSP90 antagonist, 17-AAG in malignant human glioma cell lines. ZD1839 independently produced a dose-dependent inhibition of cellular proliferation in glioma cells grown in culture with time- and dose-dependent accumulation of cells in G(1) phase of the cell cycle on flow cytometric analysis, although the concentrations required for optimal efficacy were at or above the limits of clinically achievable levels. Because the heat shock protein (HSP) is involved in the conformational maturation of a number of signaling proteins critical to the proliferation of malignant glioma cells, we hypothesized that the HSP90 inhibitor 17-AAG would potentiate ZD 1839-mediated glioma cytotoxicity by decreasing the activation status of EGF receptor, as well as down regulating the levels of other relevant signaling effectors. We, therefore, examined the effects of ZD1839 and 17-AAG, alone and in combination, on signal transduction and apoptosis in a series of malignant glioma cell lines. Simultaneous exposure to these inhibitors significantly induced cell death and quantitative analysis revealed that interaction between ZD1839 and 17-AAG-induced cytotoxicity was synergistic, leading to a pronounced increase in active caspase-3 and PARP cleavage. No significant growth inhibition or caspase activation was seen in control cells. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and a significant downregulation of EGFR receptor, Raf-1 and mitogen activated protein kinase (MAPK). Cells exposed to 17-AAG and ZD1839 displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that ZD1839, an EGF receptor tyrosine kinase inhibitor, plays a critical role in regulating the apoptotic response to 17-AAG and that multi-site targeting of growth signaling and cell survival pathways could provide a potent strategy to treat patients with malignant gliomas.
Mol Carcinog 2006 May
PMID:Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growth. 1655 Jun 10

The present data showed that 10-methoxy-9-nitrocamptothecin (MONCPT), a family of camptothecin analogues, possessed high antitumor activity in vitro and in vivo. Cytotoxicity assays showed that MONCPT was a potential and highly efficient antitumor compound with IC50 values of 0.1 to 500 nmol/L in nine tumor cell lines. The high cytotoxic potency of MONCPT was paralleled with its ability to increase the cellular accumulation of DNA damage. DNA relaxation assay also showed that MONCPT exerted high potency as a topoisomerase I inhibitor. Moreover, administration of MONCPT (5-20 mg/kg) for 15 to 17 days significantly inhibited tumor growth in human androgen-independent prostate tumor (PC3) and human non-small cell lung tumor (A549) xenografts; the inhibition rates ranged from 29.6% to 98%. The cytotoxic effect of 1,000 nmol/L of MONCPT in PC3 cells was associated with causing an arrest in G0-G1 phase, whereas that of 10 and 100 nmol/L MONCPT was relative to a persistent block in G2-M phase. Furthermore, down-regulation of CDK2, CDK4, and cyclin D1 was observed in PC3 cells treated with 1,000 nmol/L of MONCPT, whereas overexpression of CDK7, CDK1, and cyclin B1 was seen in PC3 cells treated with 10 and 100 nmol/L of MONCPT. These results suggested that cell cycle regulation might contribute to the anticancer properties of MONCPT and strongly support the further anticancer development of MONCPT.
Mol Cancer Ther 2006 Apr
PMID:Potent antitumor activity of 10-methoxy-9-nitrocamptothecin. 1664 67

Treatment of cells with carcinogen Benzo[a]pyrene (B[a]P) allows cells to evade G1 arrest and induces cells abnormal proliferation. However, the mechanisms of its action at cellular level are not well understood. To address this question, normal human embryo lung diploid fibroblasts (HELF) were selected in the present study. We found that exposure of cells with 2.5 microM of B[a]P for 24 h resulted in a decrease of G1 population by 11.9% (P < 0.05) and a increase of S population by 17.2% (P < 0.05). Treatment of cells with B[a]P also caused dose-related activation of MAPK and induction of cyclin D1 protein expression, whereas the CDK4 protein levels were not significantly affected by B[a]P. Overexpression of cyclin D1 protein stimulated by B[a]P was significantly inhibited by 50 microM AG126 (an inhibitor of ERK1/2), but not by 25 microM SP600125 (an inhibitor of JNK1/2) or 5 microM SB203580 (an inhibitor of p38 mapk), suggesting that B[a]P-induced cyclin D1 expression was only regulated by ERK1/2 pathway. However, AG126, SP600125 or SB203580 led to cell cycle significantly arrested in G1 phase, indicating that ERK1/2, JNK1/2 and p38 mapk pathways are all required for B[a]P-induced G1/S transition. In addition, HELF cells transfecting with antisense cyclin D1 cDNA or antisense CDK4 cDNA showed significantly G1 arrest after B[a]P stimulation. These results suggested that B[a]P exposure accelerated the G1-->S transition by activation of MAPK signaling pathways. Cyclin D1 and CDK4 are rate-limiting regulators of the G1-->S transition and expression of cyclin D1 is predominantly regulated by ERK1/2 pathway in HELF cells.
Mol Cell Biochem 2006 Jul
PMID:Benzo[a]pyrene-induced cell cycle progression is through ERKs/cyclin D1 pathway and requires the activation of JNKs and p38 mapk in human diploid lung fibroblasts. 1669 26

Inactivation of the Rb-mediated G1 control pathway is a common event found in many types of human tumors. To test how the Rb pathway interacts with other pathways in tumor suppression, we characterized mice with mutations in both the cyclin-dependent kinase (CDK) inhibitor p18 Ink4c and the lipid phosphatase Pten, which regulates cell growth. The double mutant mice develop a wider spectrum of tumors, including prostate cancer in the anterior and dorsolateral lobes, with nearly complete penetrance and at an accelerated rate. The remaining wild-type allele of Pten was lost at a high frequency in Pten+/- cells but not in p18+/- Pten+/- or p18-/- Pten+/- prostate tumor cells, nor in other Pten+/- tumor cells, suggesting a tissue- and genetic background-dependent haploinsufficiency of Pten in tumor suppression. p18 deletion, CDK4 overexpression, or oncoviral inactivation of Rb family proteins caused activation of Akt/PKB that was recessive to the reduction of PTEN activity. We suggest that p18 and Pten cooperate in tumor suppression by constraining a positive regulatory loop between cell growth and cell cycle control pathways.
Mol Cell Biol 2006 Jun
PMID:p18 Ink4c and Pten constrain a positive regulatory loop between cell growth and cell cycle control. 1673 22

Two distinct mitogenic modes coexist in thyroid epithelial cells. TSH via cAMP induces proliferation and differentiation expression, whereas growth factors including epidermal growth factor (EGF) induce proliferation and dedifferentiation. Divergent models of TSH/cAMP-dependent mitogenesis have emerged from different thyroid cell culture systems. In the FRTL-5 rat cell line, cAMP cross-signals with transduction pathways of growth factors to induce cyclin D1 and p21(cip1) and down-regulate p27(kip1). By contrast, in canine primary cultures, mitogenic pathways of cAMP and growth factors are fully distinct. cAMP does not induce D-type cyclins and p21, it up-regulates p27, and it stimulates the formation and activity of cyclin D3-cyclin-dependent kinase (CDK) 4 complexes. In primary cultures of normal human thyrocytes, EGF + serum increased cyclin D1 and p21 accumulation, and it stimulated the assembly and activity of cyclin D1-CDK4-p21 complexes. By contrast, TSH repressed or did not induce cyclin D1 and p21, and it rather up-regulated p27. TSH did not increase cyclin D1-CDK4 activity, but it stimulated the activating phosphorylation of CDK4 and the pRb-kinase activity of preexisting cyclin D3-CDK4 complexes. As recently demonstrated in dog thyrocytes and other systems, cyclin D1 and cyclin D3 differently oriented the site specificity of CDK4 pRb-kinase activity, which might differently impact some pRb functions. Cyclin D1 or cyclin D3 are thus differentially used in the distinct mitogenic stimulations by growth factors or TSH, and potentially in hyperproliferative diseases generated by the overactivation of their respective signaling pathways. At variance with dog thyroid primary cultures, rat thyroid cell lines might not be valid models of TSH-dependent mitogenesis of human thyrocytes.
Mol Endocrinol 2006 Dec
PMID:Differential utilization of cyclin D1 and cyclin D3 in the distinct mitogenic stimulations by growth factors and TSH of human thyrocytes in primary culture. 1691 40


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