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 examined the role of early allogeneic hematopoietic stem cell transplantation in patients with chronic phase chronic myelogenous leukemia (CML) who enter a complete cytogenetic remission with imatinib mesylate. Three kinds of data were used to examine the effect of the outcome of current BCR-ABL inhibitor treatment compared to early allogeneic stem cell transplantation: (1) the life expectancy of the general population of the United States as a function of age, (2) the life expectancy of CML patients as a function of the age of patients treated with imatinib mesylate (imatinib) who achieve a complete cytogenetic remission, and (3) the life expectancy of patients with CML treated with matched-related or matched-unrelated stem cell transplantation as a function of age, derived from data provided by the Center for International Blood and Marrow Transplant Research (CIBMTR). We also considered separately the transplant results of the Fred Hutchinson Cancer Research Center (FHCRC), which are substantially better than the "average" outcome from the CIBMTR. We have calculated the projected life expectancy from the age at which patients with CML enter complete cytogenetic remission with imatinib and that of those who receive allogeneic stem cell transplantation. The outcome with imatinib therapy of newly diagnosed patients with CML has been documented for only 4 and 1/2 years, whereas transplant data were available for up to 25 years. Thus, in order to compare life expectancy and 10-year survival probability, it was necessary to extrapolate the imatinib data. A basis for extrapolation is offered and conservative estimates have been used for comparison. Our best estimate is that patients receiving imatinib who have a complete cytogenetic remission have a higher projected probability of 10-year survival than patients who are transplanted, based on results provided by the CIBMTR, and have about the same probability compared to the data from the Fred Hutchinson Cancer Center for patients in the 30- to 60-year-old range. The mathematical approach used here permits reexamining the analysis using future data on BCR-ABL inhibitor therapy or allogeneic stem cell transplantation therapy or both.
Blood Cells Mol Dis
PMID:Early allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era: a preliminary assessment. 1690 48

Despite the positive results achieved by Imatinib mesylate (Imatinib) in the treatment of chronic myeloid leukemia (CML), over the past several years, Imatinib does not eradicate the leukemic clone. The long-term duration of response to the drug is not known. Long-term follow-up of CML patients treated with Imatinib will ultimately define the durability of such treatment and the frequency of reemergence of progressive disease. We present the results of a 6-year follow-up of 40 CML patients either in chronic or accelerated phase who obtained a durable (>6 months) complete cytogenetic remission (CCyR) after treatment with Imatinib in a single center. In 34 cases CCyR was obtained at an Imatinib dose of 400-600 mg/day and in 6 cases after a dose increase to 600-800 mg/day. At a median follow-up of 68 months, 6 cytogenetic relapses (15%) were observed. No progressions to more advanced phases of disease have been detected during the follow-up period. Cytogenetic relapse was predicted by either a decrease in the amount of BCR-ABL transcript of less than 2 logs after the achievement of CCyR (p=0.0041) or a time-to-CCyR of more than 12 months (p<0.0001). This 6-year follow-up of the efficacy of Imatinib therapy in CML patients who obtained a durable CCyR indicates that the relapses rate is low over this period of observation and that the rate of relapse does not increase over time.
Blood Cells Mol Dis
PMID:The achievement of durable complete cytogenetic remission in late chronic and accelerated phase patients with CML treated with Imatinib mesylate predicts for prolonged response at 6 years. 1690 6

The identification of organs bearing luciferase activity by in vivo bioluminescence imaging (BLI) is often difficult, and ex vivo imaging of excised organs plays a complementary role. This study investigated the importance of exposure to the atmosphere in ex vivo BLI. Mice were inoculated with murine pro-B cell line Ba/F3 transduced with firefly luciferase and p190 BCR-ABL. They were killed following in vivo BLI, and whole-body imaging was done after death and then after intraperitoneal air injection. In addition, the right knee was exposed and imaged before and after the adjacent bones were cut. Extensive light signals were seen on in vivo imaging. The luminescence disappeared after the animal was killed, and air injection restored the light emission from the abdomen only, suggesting a critical role of atmospheric oxygen in luminescence after death. Although no substantial light signal at the right knee was seen before bone cutting, light emission was evident after cutting. In conclusion, in ex vivo BLI, light emission requires exposure to the atmosphere. Bone destruction is required to demonstrate luciferase activity in the bone marrow after death.
Mol Imaging
PMID:Light emission requires exposure to the atmosphere in ex vivo bioluminescence imaging. 1695 18

Employing methods of cell biology and proteome analysis tools, we examined effects of an inhibitor of histone deacetylases, sodium butyrate (SB), on the proliferation/differentiation characteristics of chronic myelogenous leukemia (CML)-derived cells K562. SB suppressed proliferation of K562 cells by inducing cell cycle arrest in G1 phase, which was followed by their transition to G0 phase (decrease of Ki-67 antigen-positive cells) and erythroid differentiation (increased glycophorin A expression and synthesis of hemoglobins). Neither terminal apoptosis (low counts of TUNEL-positive cells) nor necrosis (moderate counts of propidium iodide-positive cells) occurred. Importantly, SB attenuated protein expression of CML-related chimeric kinase BCR-ABL that is responsible for the deregulated proliferation of CML cells. The proteomic analysis (2-D electrophoresis combined with MALDI-TOF mass spectrometry and/or Western blotting) revealed several proteins that were differentially expressed or their mobility was altered due to butyrate treatment, namely, HSP90, HSP70, p23, cyclophilin A (CYPA), prefoldin2 (PFD2) and alpha-, gamma-, epsilon-human globin chains. Perturbation of HSP90 multichaperone complex of which BCR-ABL is the client protein is presumably a cause of BCR-ABL suppression. Changes in other proteins with chaperonic functions, CYPA and PFD2, may reflect SB antiproliferative and cytodifferentiation effects.
Blood Cells Mol Dis
PMID:The proteomic study of sodium butyrate antiproliferative/cytodifferentiation effects on K562 cells. 1697 90

The Rcs signalling pathway controls a variety of physiological functions like capsule synthesis, cell division or motility in prokaryotes. The Rcs regulation cascade, involving a multi-step phosphorelay between the two membrane-bound hybrid sensor kinases RcsC and RcsD and the global regulator RcsB, is, up to now, one of the most complicated regulatory systems in bacteria. To understand the structural basis of Rcs signal transduction, NMR spectroscopy was employed to determine the solution structure of the RcsC C terminus, possessing a phosphoreceiver domain (RcsC-PR), and a region previously described as a long linker between the histidine kinase domain of RcsC (RcsC-HK) and the RcsC-PR. We have found that the linker region comprises an independent structural domain of a new alpha/beta organization, which we named RcsC-ABL domain (Alpha/Beta/Loop). The ABL domain appears to be a conserved and unique structural element of RcsC-like kinases with no significant sequence homology to other proteins. The second domain of the C terminus, the RcsC-PR domain, represents a well-folded CheY-like phosphoreceiver domain with the central parallel beta-sheet covered with two alpha-helical layers on both sides. We have mapped the interaction of RcsC-ABL and RcsC-PR with the histidine phosphotransfer domain (HPt) of RcsD. In addition we have characterized the interaction with and the conformational effects of Mg2+ and the phosphorylation mimetic BeF(-)(3) on RcsC-ABL and RcsC-PR.
J Mol Biol 2006 Nov 17
PMID:A new structural domain in the Escherichia coli RcsC hybrid sensor kinase connects histidine kinase and phosphoreceiver domains. 1700 98

Arsenic trioxide (As(2)O(3)) exhibits important antitumor activities in vitro and in vivo, but the precise mechanisms by which it induces its effects are not known. We provide evidence that during treatment of BCR-ABL-expressing cells with As(2)O(3), there is activation of a cellular pathway involving the p70 S6 kinase (p70S6K). Our data show that p70S6K is rapidly phosphorylated on Thr(421) and Ser(424) and is activated in an As(2)O(3)-inducible manner. The mammalian target of rapamycin (mTOR) is also phosphorylated/activated in an As(2)O(3)-inducible manner, and its activity is required for downstream engagement of p70S6K. p70S6K subsequently phosphorylates the S6 ribosomal protein on Ser(235)/Ser(236) and Ser(240)/Ser(244) to promote initiation of mRNA translation. Treatment of chronic myelogenous leukemia-derived cell lines with As(2)O(3) also results in phosphorylation of the 4E-BP1 repressor of mRNA translation on Thr(37)/Thr(46) and Thr(70), sites required for its deactivation and its dissociation from the eukaryotic initiation factor 4E complex to allow cap-dependent mRNA translation. In studies to determine the functional relevance of this pathway, we found that inhibition of mTOR and downstream cascades enhances induction of apoptosis by As(2)O(3). Consistent with this, the mTOR inhibitor rapamycin strongly potentiated As(2)O(3)-mediated suppression of primitive leukemic progenitors from the bone marrow of chronic myelogenous leukemia patients. Altogether, our data show that the mTOR/p70S6K pathway is activated in a negative feedback regulatory manner in response to As(2)O(3) in BCR-ABL-transformed cells and plays a key regulatory role in the induction of anti-leukemic responses.
Mol Cancer Ther 2006 Nov
PMID:Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells. 1712 28

In normal cells, signaling pathways are tightly regulated. However, when they are aberrantly activated, certain pathways are capable of causing diseases. In many tumors, the aberrantly activated signaling proteins include members of the epidermal growth factor receptor family, the Ras proteins, protein kinase C isoenzymes, BCR-ABL fusion protein as well as transcription factors such as signal transducers and activators of transcriptions and Myc. Accordingly, deregulation of these signaling proteins holds promise for the development of new anticancer drugs. Studies in vitro and in disease-relevant models demonstrated that blocking the activation of a key target in a constitutively activated signaling pathway could reverse disease phenotype. Moreover, constitutive activation of the target alone is sufficient to induce relevant disease phenotype. Notably, the most dramatic therapeutic advances in cancer therapy during the last decade have come from agents targeted against active thyrosine kinases. These include imatinib (anti-BCR-ABL), gefitinib (anti-EGF receptor), and herpetin (anti-ErbB-2). Here, some selected validated and drugable targets are summarized.
Methods Mol Biol 2007
PMID:Druggable signaling proteins. 1717 5

Patients with chronic myeloid leukemia harbor the chromosomal translocation t(9;22), which corresponds to fusion of the BCR and ABL genes at the DNA level. The translated fusion product is an oncogenic protein with increased ABL tyrosine kinase activity causing cell transformation. To date, reverse transcriptase-polymerase chain reaction is considered the most sensitive method available for detecting low copy numbers of the BCR-ABL gene fusion. Recently, Cepheid introduced its GeneXpert-based assay for the identification of the BCR-ABL gene fusion in cells from blood samples. This system comprises a walk-away self-contained instrument that combines cartridge-based microfluidic sample preparation with reverse transcriptase-polymerase chain reaction-based fluorescent signal detection and BCR-ABL and ABL Ct (threshold cycle) determination. The difference between the BCR-ABL Ct and ABL Ct (DeltaCt) is expected to represent the ratio of the two populations of mRNAs and ultimately the percentage of neoplastic cells present. We tested whether this BCR-ABL fusion detection system could be used as a clinical diagnostic tool for monitoring patients with minimal residual disease of chronic myelogenous leukemia. We report similar performance characteristics, including limit of detection, specificity, sensitivity, and precision, of this automated BCR-ABL fusion detection system to those of a manual TaqMan reverse transcriptase-polymerase chain reaction-based test.
J Mol Diagn 2007 Apr
PMID:Evaluation of the Cepheid GeneXpert BCR-ABL assay. 1738 14

FSH regulates ovarian granulosa cell differentiation not only by activating adenylyl cyclase and protein kinase A (PKA) but also by other complex mechanisms. Using primary rat granulosa cell cultures, we provide novel evidence that FSH rapidly activates two small GTP-binding proteins RAP1 and RAS. FSH activation of RAP1 requires cAMP-mediated activation of exchange factor activated by cAMP/RAPGEF3 whereas FSH activation of RAS and downstream signaling cascades involves multiple factors. Specifically, FSH activation of RAS required Rous sarcoma oncogene (SRC) family tyrosine kinase (SFK) and epidermal growth factor receptor (EGFR) tyrosine kinase activities but not PKA. FSH-induced phosphorylation of ERK1/2 was blocked by dominant-negative RAS as well as by inhibitors of EGFR tyrosine kinase, metalloproteinases involved in growth factor shedding, and SFKs. In contrast, FSH-induced phosphorylation of protein kinase B (PKB/AKT) and the Forkhead transcription factor, FOXO1a occurred by SFK-dependent but RAS-independent mechanisms. The SFKs, c-SRC and FYN, and the SRC-related tyrosine kinase ABL were present and phosphorylated rapidly in response to FSH. Lastly, the EGF-like factor amphiregulin (AREG) activated RAS and ERK1/2 phosphorylation in granulosa cells by mechanisms that were selectively blocked by an EGFR antagonist but not by an SFK antagonist. However, AREG-mediated phosphorylation of PKB and FOXO1a required both EGFR and SFK activation. Moreover, we show that FSH induces AREG and that activation of the EGFR impacts granulosa cell differentiation and the expression of genes characteristic of the luteal cell phenotype. Thus, FSH orchestrates the coordinate activation of three diverse membrane-associated signaling cascades (adenylyl cyclase, RAS, and SFKs) that converge downstream to activate specific kinases (PKA, ERK1/2, and PKB/FOXO1a) that control granulosa cell function and differentiation.
Mol Endocrinol 2007 Aug
PMID:Follicle-stimulating hormone induces multiple signaling cascades: evidence that activation of Rous sarcoma oncogene, RAS, and the epidermal growth factor receptor are critical for granulosa cell differentiation. 1753 7

Data are presented that indicate the dynamic changes of nutrients in milk from three free ranging African elephant (Loxodonta africana africana) cows during lactation. At the respective collection times of 12, 14 and 18 months of lactation the nutrient content was 47.3, 52.0 and 68.6 g protein; 60.7, 87.4 and 170.8 g fat; 1.6, 2.1 0.5 g lactose and 20.9, 21.5 and 8.6 g oligosaccharides per kg milk. The protein fraction respectively consisted of 18.0, 31.7 and 45.9 g caseins/kg milk and of 29.3, 20.3 and 22.7 g whey proteins/kg milk. Electrophoresis and identification of protein bands showed that polymorphs of one whey protein may be present in elephant's milk similar to polymorphs of alpha-lactalbumin found in cow's milk. From the middle of the lactation time lactose was replaced by oligosaccharides as major carbohydrate, and the major compound of these was identified as isoglobotriose by 1H NMR spectroscopy. The lipid fraction contains a high content, of capric and lauric acids, approximately 70% of the total fatty acids, and low content of myristic, palmitic and oleic acids. During these lactation times the content of short chain fatty acids, capric and caprylic acids increased, while fatty acids lauric acid and longer decreased.
Comp Biochem Physiol B Biochem Mol Biol 2007 Sep
PMID:Milk composition of three free-ranging African elephant (Loxodonta africana africana) cows during mid lactation. 1761 52


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