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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin proteasome system plays a fundamental role in the regulation of cellular processes by degradation of endogenous proteins. Proteasomes are localized in both, the cytoplasm and the cell nucleus, however, little is known about nuclear proteolysis. Here, fluorogenic precursor substrates enabled detection of proteasomal activity in nucleoplasmic cell fractions (turnover 0.0541 microM/minute) and nuclei of living cells (turnover 0.0472 microM/minute). By contrast, cell fractions of nucleoli or nuclear envelopes did not contain proteasomal activity. Microinjection of ectopic fluorogenic protein DQ-ovalbumin revealed that proteasomal protein degradation occurs in distinct nucleoplasmic foci, which partially overlap with signature proteins of subnuclear domains, such as splicing speckles or promyelocytic leukemia bodies, ubiquitin, nucleoplasmic proteasomes and RNA polymerase II. Our results establish proteasomal proteolysis as an intrinsic function of the cell nucleus.
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PMID:Proteasomes degrade proteins in focal subdomains of the human cell nucleus. 1624 32

Coenzyme Q (CoQ) is an isoprenoid quinine that functions as an electron carrier in the mitochondrial respiratory chain in eukaryotes. CoQ having shorter isoprenoid chains, especially CoQ1 and CoQ2, selectively inhibited the in vitro activity of eukaryotic DNA polymerase (pol) gamma, which is a mitochondrial pol. These compounds did not influence the activities of nuclear DNA replicative pols such as alpha, delta and epsilon, and nuclear DNA repair-related pols such as beta, eta, iota, kappa and lambda. CoQ also inhibited DNA topoisomerase II (topo II) activity, although the enzymatic characteristics, including modes of action, amino acid sequences and three-dimensional structures, were markedly different from those of pol gamma. These compounds did not inhibit the activities of procaryotic pols such as Escherichia coli pol I, and other DNA metabolic enzymes such as human immunodeficiency virus reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. CoQ1, which has the shortest isoprenoid chains, had the strongest inhibitory effect on pol gamma and topo II activities among CoQ1-CoQ10, with 50% inhibitory concentration (IC50) values of 12.2 and 15.5 microM, respectively. CoQ1 could prevent the growth of human promyelocytic leukemia cells, HL-60, and the 50% lethal dose (LD50) value was 14.0 microM. The cells were halted at S phase and G1 phase in the cell cycle, and suppressed mitochondrial proliferation. From these results, the relationship between the inhibition of pol gamma/topo II and cancer cell growth by CoQ is discussed.
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PMID:Inhibitory effect of coenzyme Q on eukaryotic DNA polymerase gamma and DNA topoisomerase II activities on the growth of a human cancer cell line. 1686 5

Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is composed of 855 amino acids, contains 15 tetratricopeptide repeat motifs, and associates with Cockayne syndrome group A and B proteins and RNA polymerase II, as well as XPA. In vitro and in vivo studies showed that XAB2 is involved in pre-mRNA splicing, transcription, and transcription-coupled DNA repair, leading to preimplantation lethality, and is essential for mouse embryogenesis. Retinoids are effective for the treatment of preneoplastic diseases including xeroderma pigmentosum and other dermatologic diseases such as photoaging. We therefore focused on defining the effect of XAB2 on cellular differentiation in the presence of ATRA treatment. In the present study, we showed that overexpression of XAB2 inhibited ATRA-induced cellular differentiation in human rhabdomyosarcoma cell line, and that knockdown of XAB2 by small interfering RNA (siRNA) increased ATRA-sensitive cellular differentiation in the human promyelocytic leukemia cell line HL60 at both physiologic (10(-9)-10(-8) mol/L) and therapeutic (10(-7) mol/L) concentrations of ATRA. Moreover, we found that XAB2 was associated with retinoic acid receptor alpha (RARalpha) and histone deacetylase 3 in the nuclei. Finally, using siRNA against XAB2, we showed that the ATRA-resistant neuroblastoma cell line IMR-32 underwent cellular differentiation induced by ATRA at a therapeutic concentration (10(-6) mol/L). These results strongly suggest that XAB2 is a component of the RAR corepressor complex with an inhibitory effect on ATRA-induced cellular differentiation and that XAB2 plays a role in ATRA-mediated cellular differentiation as an important aspect of cancer therapy.
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PMID:Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-sensitive and -resistant cancer cells. 1728 34

A 18-year-old man was diagnosed with acute promyelocytic leukemia (APL). The conventional cytogenetic analysis revealed normal karyotype 46, XY, t(15; 17). Reverse transcriptase polymerase chain reaction (RTPCR) identified PML-RARa chimeric transcripts. Complete remission (CR) was attained with 3 induction courses of Ara-C, daunorubicin and all-trans retinoic acid (ATRA). Three years later the patient relapsed. The blasts in bone marrow aspirate at relapse had AML-M3 morphology, and RT-PCR was positive for PML-RARa transcripts. The patient was treated with ATRA and daunorubicin without success. Two months later the blasts in bone marrow aspirate showed AML-M2 morphology, the karyotype was 47, XY, +8 and RT-PCR revealed the presence of AML1-ETO transcripts and absence of PML-RARa transcripts. The patient attained second CR with 3 induction courses -a course with Ara-C and daunorubicin and 2 courses with idarubicin, Ara-C and etoposide.
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PMID:Clonal heterogeneity in a patient with acute promyelocytic leukemia. 1741 15

In the acute promyelocytic leukemia cell line, NB4, activation of the CD44 receptor triggers apoptosis. This pathway does not operate in the retinoid-maturation-resistant NB4-LR1 subclone. In this work, we show that the CD44 gene is silenced in these cells. The molecular defect involves DNA methylation of cytosine phosphate guanine (CpG) island and underacetylation of histone H3 at CD44 promoter. The methylating inhibitor 5-aza-CdR and cyclic AMP (cAMP) reverse the CD44 gene silencing. Contrary to 5-aza-CdR, cAMP does not induce DNA demethylation or histone modification at the CD44 promoter, whereas an H3pS10/AcK14 dual modification is observed on a global level. cAMP also induces the expression of c-Jun transcription factor and its recruitment at the CD44 promoter. Chromatin immunoprecipitation assays further show the association of brahma (Brm), a subunit of SWI/SNF chromatin-remodelling complex involved in the crosstalk between transcription and RNA polymerase II (RNA Pol II) processing, as well as the binding of phosphorylated RNA Pol II to the proximal promoter region of CD44. Finally, our study reveals that cAMP re-establishes the CD44-mediated cell death signalling. We propose that one of the actions of cAMP in restoring normal cell phenotype of leukaemia cells may consist in a broad trans-reactivation of silenced genes, despite marked hypermethylation of their promoters, as illustrated here with CD44 re-expression.
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PMID:Re-expression of DNA methylation-silenced CD44 gene in a resistant NB4 cell line: rescue of CD44-dependent cell death by cAMP. 1809 16

Treatment of acute promyelocytic leukemia (APL) with a combination of anthracycline-based chemotherapy and all-trans retinoic acid (ATRA) leads to very high rates of complete remission and survival. There are only a limited number of publications on the development of therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia during follow-up of APL. Although drugs targeting at DNA-topoisomerase II characteristically induce translocations involving 11q23, this was seldom seen in patients treated for APL. We report on a patient initially diagnosed with APL. Response to therapy was monitored by fluorescence in situ hybridization (FISH) and reverse-transcriptase polymerase chain reaction for the PML-RARalpha rearrangement. Consecutive samples showed a swift and complete reduction of PML-RARalpha rearranged cells. Twenty months after diagnosis, however, conventional cytogenetics revealed a complex karyotype with a translocation involving 11q23 and loss of chromosomes 7q and Xq. FISH analysis with the MLL probe identified 2q37 (harboring the SEPT2 gene) as the translocation partner of chromosome 11. We consider the rather unique t(2;11)(q37;q23) as the primary event causing therapy-related MDS in our patient. This case stresses the importance of conventional karyotyping to be performed on a regular basis in all treated APL patients for the early detection of chromosomal aberrations that indicate the development of therapy-related MDS or acute myeloid leukemia.
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PMID:Translocation (2;11)(q37;q23) in therapy-related myelodysplastic syndrome after treatment for acute promyelocytic leukemia. 1820 42

Submicroscopic deletions of the PML-RARA fusion genes constitute rare rearrangements in acute promyelocytic leukemia (APL). We describe a rare case of APL carrying a novel complex translocation involving chromosomes 15, 17, and 18 associated with a submicroscopic deletion of the 5' part of the RARA gene, as evidenced by fluorescence in situ hybridization (FISH). A PML/RARA dual-fusion probe did not reveal the RARA-PML fusion signal on the der(17q), usually detected in the typical t(15;17). The RARA break-apart probe showed a deletion hybridization pattern with loss of the signal corresponding to the 5' portion of the RARA gene. Reverse transcriptase-polymerase chain reaction confirmed the absence of the fusion RARA-PML transcript. The patient achieved complete remission, but died during consolidation therapy, 2 months after diagnosis. To our knowledge, this is the first reported case of APL with a complex variant t(15;17) involving chromosome 18 at band q12 and one of the very rare described cases displaying a submicroscopic deletion of the RARA 5' region. Further cases are needed to delineate the incidence of submicroscopic deletions in APL and elucidate their prognostic impact.
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PMID:5'RARA submicroscopic deletion from new variant translocation involving chromosomes 15, 17, and 18, in a case of acute promyelocytic leukemia. 1832 52

Acute promyelocytic leukemia (APML) is a well-characterized malignancy with typical clinico-hematological and molecular features. However, Indian data on this malignancy are limited. This study was conducted to determine the clinico-hematological profile of APML in India. Thirty-five patients with APML presenting to Hematology Department, AIIMS, New Delhi, between July 2003 and June 2005 were evaluated for presenting clinical features, hemogram, peripheral smear, bone marrow morphology and cytochemistry. Reverse transcriptase PCR (RT-PCR) for PML-RARalpha was done in all cases. Male-to-female ratio was 0.9:1 (males--17 and females--18) with median age 25 years (range 11-57 years). Presenting features included anemia, bleeding, fever, gum hypertrophy and scrotal ulceration. All cases showed hypergranular abnormal promyelocytes. Median hemoglobin was 6.3 g/dL (range - 3.0-9.0 g/dL), total leukocyte count (TLC) was 33.88 x 10(9) /L (range - 1-170 x 10(9) /L). Platelet count was 28 x 10(9) /L (range - 4-170 x 10(9) /L). All cases were positive for myeloperoxidase and sudan black (SB), whereas 60% cases also showed non specific esterase (NSE) positivity with 40% cases being fluoride sensitive. RT-PCR showed PML-RARalpha in 33/35 cases with the bcr3 isoform being present in 24/33 positive cases (72.7%). The two cases negative for PML-RARalpha showed typical morphology and responded to ATRA. On statistical analysis, no correlation was found between bcr isoform and TLC, platelet count, age sex and early death. Unusual features included gum hypertrophy and scrotal ulceration at presentation and high median presenting TLC (33.8 x 10(9) /L). There was, however, no microgranular variant. Another interesting feature was a high incidence of NSE positivity (60%), which was fluoride sensitive in 40%. Moreover, the bcr3 isoform was significantly overexpressed (72.7%) in comparison to other studies. APML in India has certain unusual features, which may reflect a different biology.
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PMID:Does acute promyelocytic leukemia in Indian patients have biology different from the West? 1872 85

Nested reverse-transcriptase polymerase chain reaction (rt-PCR) was performed on 58 leukemia patients at BIRDEM Laboratory, as a pioneering work in Bangladesh. Thirty of themwere examined for the presence of BCR-ABL being clinically and morphologically diagnosed as chronic myeloid leukemia (CML) and 28 for PML-RARalpha fusion transcripts being clinically and morphologically diagnosed as acute promyelocytic leukemia (APL/ AML M3). The cases were selected for targeted therapy with imatinib mesylate and all-Trans retinoic acid (ATRA) to treat CML and APL respectively. Samples were received either before commencement or during therapy. In the positive cases, amplified DNA products were visible after gel electrophoresis and were reported accordingly. In case of BCR-ABL, positive results were found for five out of six (83.33%) untreated cases and 11 out of 24 (45.83%) treated cases. Positive results for PML-RARalpha were found for 12 out of 14 (85.70%) untreated cases and 11 out of 16 (68.75%) treated cases. A strong positive correlation was found between duration of treatment and negativity of PCR results in both the cases. In present times, the detection of minimal residual disease in patients undergoing treatment for hematological malignancies has become an important goal, not only to monitor the effectiveness of therapy but also to detect an impending relapse. This is the first time in Bangladesh that rt-PCR method is being employed to detect or monitor the presence of abnormal fusion genes in hematological malignancies.
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PMID:Rt-PCR method for diagnosis and follow-up of hematological malignancies: first approach in Bangladesh. 1878 70

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia. Submicroscopic insertion of RARalpha into PML, resulting in PML-RARalpha from derivative chromosome 15, has been rarely reported. Herein, we describe a functional PML-RARalpha transcript from the long arm of derivative chromosome 17 in a patient with microgranular APL. The conventional karyotype showed normal chromosomes 15 and 17. It is interesting that interphase and metaphase fluorescence in situ hybridizations demonstrated a fusion signal on the long arm of one chromosome 17 homolog, with both PML and RARalpha still present on chromosomes 15 and 17, respectively, although the signal on one chromosome 15 was weaker, indicating partial loss of the PML gene. Reverse transcriptase-polymerase chain reaction revealed a transcript corresponding to a break cluster region 3 (bcr3) short form PML-RARalpha. To the best of our knowledge, this is the first report of an APL with a bcr3/short form PML-RARalpha transcript generated from derivative chromosome 17 due to submicroscopic insertion of the PML gene into the RARalpha locus.
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PMID:A bcr3/short form PML-RARalpha transcript in an acute promyelocytic leukemia resulted from a derivative chromosome 17 due to submicroscopic insertion of the PML gene into the RARalpha locus. 1909 67


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