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:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysyl oxidase, an extracellular enzyme involved in the maturation of collagen and elastin, also appears to function as a phenotypic suppressor of transformation by the ras gene product, p21. Genomic clones of the mouse lysyl oxidase gene have been isolated, analyzed, and sequenced. Lysyl oxidase appears to be a single-copy gene, organized into seven exons and six introns, and spans approximately 14 kb of the mouse genome. The gene encodes two messages, sized at about 4.8 and 3.8 kb, that differ in the length of the untranslated sequence at the 3' end of the gene. All of the 3' untranslated sequence and the polyadenylation signals are contained in exon VII; there is no evidence of alternate splicing. Primer extension and ribonuclease protection experiments revealed two sites of transcription initiation in a region with sequence motifs characteristic of a promoter, which was upstream and adjacent to the 5' untranslated sequence found in the cDNA.
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PMID:Structure of the mouse lysyl oxidase gene. 810 Feb 14

The retinoblastoma tumor suppressor gene product (pRb) is involved in controlling cell cycle progression from G1 into S. pRb functions, in part, by regulating the activities of several transcription factors, making pRb involved in the transcriptional control of cellular genes. Transient-transfection assays have implicated pRb in the transcription of several genes, including c-fos, the interleukin-6 gene, c-myc, cdc-2, c-neu, and the transforming growth factor beta2 gene. However, these assays place the promoter in an artificial context and exclude the effects of far 5' upstream regions and chromosomal architecture on gene transcription. In these experiments, we have studied the role of pRb in the control of cell cycle-related genes within a chromosomal context and within the context of the G1 phase of the cell cycle. We have used adenovirus vectors to overexpress pRb in human osteosarcoma cells and breast cells synchronized in early G1. By RNase protection assays, we have assayed the effects of this virus-produced pRb on gene expression in these cells. These results indicate that pRb is involved in the transcriptional downregulation of the E2F-1, E2F-2, dihydrofolate reductase, thymidine kinase, c-myc, proliferating-cell nuclear antigen, p107, and p21/Cip1 genes. However, it has no effect on the transcription of the E2F-3, E2F-4, E2F-5, DP-1, DP-2, or p16/Ink4 genes. The results are consistent with the notion that pRb controls the transcription of genes involved in S-phase promotion. They also suggest that pRb negatively regulates the transcription of two of the transcription factors whose activity it also represses, E2F-1 and E2F-2, and that it plays a role in downregulating the immediate-early gene response to serum stimulation.
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PMID:Regulation of cellular genes in a chromosomal context by the retinoblastoma tumor suppressor protein. 967 66

We have previously shown (K. Kas et al, Nat. Genet., 15: 170-174, 1997) that the developmentally regulated zinc finger gene pleomorphic adenoma gene 1 (PLAG1) is the target gene in 8q12 in pleomorphic adenomas of the salivary glands with t(3;8)(p21;q12) translocations. The t(3;8) results in promoter swapping between PLAG1 and the constitutively expressed gene for beta-catenin (CTNNB1), leading to activation of PLAG1 expression and reduced expression of CTNNB1. Here we have studied the expression of PLAG1 by Northern blot analysis in 47 primary benign and malignant human tumors with or without cytogenetic abnormalities of 8q12. Overexpression of PLAG1 was found in 23 tumors (49%). Thirteen of 17 pleomorphic adenomas with a normal karyotype and 5 of 10 with 12q13-15 abnormalities overexpressed PLAG1, which demonstrates that PLAG1 activation is a frequent event in adenomas irrespective of karyotype. In contrast, PLAG1 was overexpressed in only 2 of 11 malignant salivary gland tumors analyzed, which suggests that, at least in salivary gland tumors, PLAG1 activation preferentially occurs in benign tumors. PLAG1 over-expression was also found in three of nine mesenchymal tumors, i.e., in two uterine leiomyomas and one leiomyosarcoma. RNase protection, rapid amplification of 5'-cDNA ends (5'-RACE), and reverse transcription-PCR analyses of five adenomas with a normal karyotype revealed fusion transcripts in three tumors. Nucleotide sequence analysis of these showed that they contained fusions between PLAG1 and CTNNB1 (one case) or PLAG1 and a novel fusion partner gene, i.e., the gene encoding the transcription elongation factor SII (two cases). The fusions occurred in the 5' noncoding region of PLAG1, leading to exchange of regulatory control elements and, as a consequence, activation of PLAG1 gene expression. Because all of the cases had grossly normal karyotypes, the rearrangements must result from cryptic rearrangements. The results suggest that in addition to chromosomal translocations and cryptic rearrangements, PLAG1 may also be activated by mutations or indirect mechanisms. Our findings establish a conserved mechanism of PLAG1 activation in salivary gland tumors with and without 8q12 aberrations, which indicates that such activation is a frequent event in these tumors.
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PMID:Conserved mechanism of PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: identification of SII as a new fusion partner gene. 1002 85

Epidemiology suggests a possible relationship between exposure to power frequency magnetic fields (EMF) and breast cancer. One mechanism through which EMF could stimulate breast cancer induction is via altered expression of oncogenes and/or tumor suppressor genes that regulate normal and neoplastic growth. To evaluate the hypothesis that EMF action in the breast is mediated by alterations in gene expression, transcript levels of c-myc and a battery of other cancer-associated genes were quantitated in human breast epithelial cells exposed to pure, linearly polarized 60 Hz EMF with low harmonic distortion. HBL-100 cells and normal (non-transformed) human mammary epithelial cells were exposed to EMF flux densities of 0.1, 1.0 and 10.0 Gauss (G) for periods ranging from 20 min to 24 h; concurrent sham controls were exposed to ambient fields (<0.001 G) only. Gene expression was quantitated using ribonuclease protection assays. EMF exposure had no statistically significant effect on basal levels of c-myc transcripts in either human breast cell model, and had no effect on alterations in c-myc expression induced by 12-O-tetradecanoylphorbol-13-acetate. Transcript levels of c-erbB-2, p53, p21, GADD45, bax, bcl-x, mcl-1, and c-fos were also unaffected by EMF exposure. These results suggest that EMF is unlikely to influence breast cancer induction through a mechanism involving altered expression of these genes.
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PMID:Gene expression in human breast epithelial cells exposed to 60 Hz magnetic fields. 1042 19

Cells respond to genotoxic stress by activation of many genes, including the tumor suppressor p53. p53 activates transcriptionally target genes, such as p21waf1 and gadd45, which can lead to cell cycle arrest, or bax, which can lead to cell death. We examined the response to genotoxic stress in two hematopoietic cell lines that harbor either wild-type (MOLT-4) or a mutant p53 with a codon 161 mutation (U266). We adapted a multiprobe RNase protection assay (RPA) to determine the steady-state RNA levels, and in combination with nuclear runoff assays, transcriptional rates of multiple stress-induced genes. We found a differential activation of growth arrest and cell death-specific p53 target genes in cells with wild-type or mutant p53. Our results show that genotoxic stress can activate the p21waf1 and gadd45 genes in both cell lines. However, the bax gene was not induced in U266 cells. Bax and gadd45 gene induction could be efficiently blocked by pretreating the cells with the antioxidant compound pyrrolidine dithiocarbamate, suggesting that oxidative stress was involved in these responses. Induction of all three genes in MOLT-4 cells was clearly at the transcriptional level, because we detected transcriptional activity by nuclear runoff RPA assays, and transfection with a consensus p53 binding sequence. U266 cells did not activate the same reporter, in spite of the upregulation of p21waf1 and gadd45 RNA levels. However, the p21waf1-reporter constructs containing 0.9 to 2.4 kb of the native p21 promoter were potently activated in U266 cells. These results indicate a differential regulation of p53 target genes in cells containing wild-type or codon 161 mutant p53.
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PMID:Differential upregulation of p53-responsive genes by genotoxic stress in hematopoietic cells containing wild-type and mutant p53. 1079 22

Human T-cell lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). T-cell transformation is mainly due to the actions of the viral phosphoprotein Tax. Tax interacts with multiple transcriptional factors, aiding the transcription of many cellular genes. Here, we report that the cyclin-dependent kinase inhibitor p21/waf1 is overexpressed in all HTLV-1-infected cell lines tested as well as in ATL and HAM/TSP patient samples. Tax was found to be able to transactivate the endogenous p21/waf1 promoter, as detected by RNase protection, as well as activate a series of wild-type and 5'-deletion constructs linked to a luciferase reporter cassette. Wild-type but not a mutant form of Tax (M47) transactivated the p21/waf1 promoter in a p53-independent manner and utilized a minimal promoter that contained E2A and TATA box sequences. The p21/waf1 protein was reproducibly observed to be complexed with cyclin A/cdk2 and not with any other known G(1), S, or G(2)/M cyclins. Functionally, the association of p21/cyclin A/cdk2 decreased histone H1 phosphorylation in vitro, as observed in immunoprecipitations followed by kinase assays, and affected other substrates, such as the C terminus of Rb protein involved in c-Abl and histone deacetylase-1 (HDAC1) regulation. Interestingly, upon the use of a stress signal, such as gamma-irradiation, we found that the p21/cyclin A/cdk2 complex was able to block all known phosphorylation sites on the Rb molecule. Finally, using elutriated cell cycle fractions and a stress signal, we observed that the HTLV-1-infected T cells containing wild-type Tax, which had been in early or mid-G(1) phase prior to gamma-irradiation, arrested in G(1) and did not undergo apoptosis. This may be an important mechanism for an oncogenic virus such as HTLV-1 to stop the host at the G(1)/S boundary and to repair the damaged DNA upon injury, prior to S-phase entry.
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PMID:Overexpression of p21(waf1) in human T-cell lymphotropic virus type 1-infected cells and its association with cyclin A/cdk2. 1090 81

The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), in human bladder cancers. In situ hybridization shows that PPARgamma mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARgamma was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor alpha (RXRalpha), a 9-cis-retinoic acid stimulated (9-cis-RA) heterodimeric partner of PPARgamma, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARgamma agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRalpha ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPAR- activators, ciglitazone and 15-deoxy-delta(12,14)-PGJ2 (15dPGJ(2)). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21(WAF1/CIP1) and p16(INK4), and reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARgamma target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP), the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARgamma is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.
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PMID:Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death. 1093 88

Induction of p53 by DNA damage results in apoptosis of teratocarcinoma cells, whereas MDM2, encoded by a p53-responsive gene, can reverse this phenotype by inhibiting p53 function. Here we report that UV (10 or 20 J/m2), but not gamma irradiation (7 or 10 Gy), caused a massive apoptosis of human teratoma Tera-2 or murine testicular carcinoma F9 cells, both of which contain wild-type p53, but not murine p53 null testicular carcinoma EB-16 cells. Most Tera-2 or F9 cells died overnight after UV but not gamma irradiation. Correlated with this phenotype was a dramatic and continuing accumulation of p53 proteins after UV but not gamma irradiation. This was attributable to UV-responsive repression of MDM2 expression, because both its protein and RNA were not detectable after UV irradiation. This UV-induced repression appeared to be specific to MDM2, because expression of other genes, such as p21, p53, or glyceraldehyde-3-phosphate dehydrogenase, was not reduced. Also, RNase protection analysis showed that a DNA region, excluding the p53 binding site, in the MDM2 promoter mediated transcriptional repression in response to UV. Thus, these results suggest that UV but not gamma irradiation can induce p53 by suppressing MDM2 expression in a p53-independent fashion and subsequently, massive cell death.
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PMID:UV but not gamma irradiation accelerates p53-induced apoptosis of teratocarcinoma cells by repressing MDM2 transcription. 1108 43

Steel factor (SLF) plus GM-CSF induces proliferative synergy in myeloid progenitors and factor-dependent cell line MO7e. We previously reported that the protein level of cyclin-dependent kinase inhibitor p21(cip1/waf1) (p21) increased synergistically when MO7e cells were stimulated with SLF plus GM-CSF and that p21 induction was required for SLF synergistic responses. Here we show that this p21 induction is regulated at the transcriptional level. Based on use of a multiprobe RNase protection assay, the synergistic increase of p21 mRNA was unique among many cell cycle regulators. While STAT5A and 5B were activated after stimulation with GM-CSF alone or SLF plus GM-CSF, there was no difference in activation between the groups. p44/42 MAP kinase (ERK1/2) was synergistically activated by SLF plus GM-CSF, but SAPK/JNK and p38 MAP kinase were not. Synergistic induction of p21 was significantly decreased with a MEK1 inhibitor, suggesting that the ERK1/2 pathway is involved in the synergistic increase of p21 after GM-CSF plus SLF stimulation.
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PMID:Transcriptional and ERK1/2-dependent synergistic upregulation of p21(cip1/waf1) associated with steel factor synergy in MO7e. 1116 74

Partial hepatectomy (PH) or toxic liver injury induces the proliferation of terminally differentiated hepatic cells to regenerate the original size of the adult liver. Previous PH liver regeneration studies showed that premature transgenic expression of the Forkhead Box M1b (FoxM1b, HFH-11B) transcription factor accelerated hepatocyte entry into DNA replication (S-phase). In this study, we used carbon tetrachloride (CCl(4)) liver injury to induce a different type of mouse liver regeneration and show that premature hepatic HFH-11B levels also accelerate the onset of hepatocyte S-phase in this injury model. Unlike PH liver regeneration, earlier hepatocyte proliferation after CCl(4) liver injury is correlated with diminished transgenic hepatic levels of p21(CIP1/WAF1) at the G1/S transition of the cell cycle. Differential hybridization of cDNA arrays and RNase protection studies determined that CCl(4) regenerating liver of transgenic mice displayed early stimulated expression of the S-phase promoting cyclin D1 and cyclin E and sustained levels of Cdc25a phosphatase genes. Compared with previous PH liver regeneration studies, our data suggest that premature expression of HFH-11B activates distinct S-phase promotion pathways in the CCl(4) liver injury model. Although proliferating transgenic hepatocytes induced by either PH or CCl(4) liver injury displayed early expression of identical M-phase cyclin genes (cyclin B1, B2, A2, and F), only CCl(4) regenerating transgenic liver exhibited earlier expression of the M-phase promoting Cdc25b. These studies suggest that CCl(4) injury of transgenic liver not only uses the same mechanisms as PH to mediate accelerated hepatocyte entry into mitosis, but also promotes M-phase entry by stimulating Cdc25b expression.
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PMID:Earlier expression of the transcription factor HFH-11B diminishes induction of p21(CIP1/WAF1) levels and accelerates mouse hepatocyte entry into S-phase following carbon tetrachloride liver injury. 1139 29


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