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)

Protein kinase C-associated kinase (PKK; DIK/RIP4) is an ankyrin-repeat containing serine/threonine receptor-interacting protein (RIP)-family kinase that can activate NFkappaB, and is required for keratinocyte development. In earlier studies, the expression of a catalytically inactive mutant of PKK in the B cell lineage resulted in a marked decrease in peripheral B cells in the spleen and a severe reduction of B-1 B cells. Here we explore the consequences of a null mutation in PKK with respect to the generation of peripheral B cell lineages and the activation of NFkappaB. We show that PKK is not required for the production of B cells in the bone marrow or for the development and maintenance of all mature B lymphocyte populations. We also show that PKK is not required for the activation of NFkappaB downstream of the BCR, CD40, or TLR-4 in B cells. Taken together, these data demonstrate that the loss of this RIP-family kinase does not compromise B lymphocyte development and maintenance, but leaves open the possibility that PKK may have a redundant role in these processes.
Mol Immunol 2006 Apr
PMID:Protein kinase C-associated kinase is not required for the development of peripheral B lymphocyte populations. 1625

Myeloproliferative disorders include several pathologies sharing the common feature of being clonal hematopoietic stem cell diseases. The molecular basis of chronic myeloid leukemia was characterized many years ago with the discovery of the t(9;22) translocation and its product the BCR-ABL oncoprotein. The recent finding of a recurrent mutation in the Janus 2 tyrosine kinase gene is a major advance in our understanding of the pathogenesis of several other myeloproliferative disorders, including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Although this work clearly identifies a frequent ( approximately 50%) subgroup of myeloproliferative disorders and explains most biological abnormalities described so far, it also raises the major question of how a single mutation can explain disease heterogeneity. Such a recurrent and unique mutation leading to a tyrosine kinase deregulation would make a suitable target for the development of specific therapies.
Trends Mol Med 2005 Dec
PMID:A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects. 1627 12

Imatinib mesylate is a major advance in the therapy of patients with chronic myelogenous leukemia (CML). Imatinib mesylate binds to the inactive conformation of BCR-ABL tyrosine kinase suppressing the Philadelphia chromosome positive clone in CML. Clinical studies have yielded impressive results in all phases of CML. With higher rates of complete cytogenetic response with imatinib, molecular monitoring of disease is now advisable in assessing response and determining prognosis. Emergence of resistance to imatinib may be manifest at the hematologic, cytogenetic, or molecular levels in patients who remain in chronic phase, or may be evidenced by the development of more advanced CML phases. Resistance and eventual clinical failure of imatinib occurs in most patients with blastic phase disease. Resistance may occur at the level of Bcr-Abl, with reduction or loss of imatinib effectiveness as a kinase inhibitor, or, despite retention of its inhibitory ability, with changes in the ability to deliver an effective dose at the cellular level, and/or, the leukemia becoming less dependent on Bcr-Abl. The various mechanisms underlying these differing, non-mutually exclusive, mechanisms of resistance must be understood to develop corresponding therapeutic remedies. We review the current data on imatinib in CML, the criteria for diagnosis of imatinib resistance, and the mechanisms that underlie such resistance in CML.
Curr Mol Med 2005 Nov
PMID:Targeting the kinase activity of the BCR-ABL fusion protein in patients with chronic myeloid leukemia. 1630 88

Protein kinases have emerged as one of the most promising targets for rational drug discovery. In a similar manner to imatinib mesylate (Gleevec), hematological malignancies offer multiple pharmacologic opportunities for manipulation of kinase-induced tumor cell proliferation. Certain kinases have been validated as targets for drug discovery in hematological malignancies (such as BCR-ABL and FLT3); other novel kinases hold considerable interest for targeted intervention: myeloid leukemias (KDR, KIT, CSF-1R, RAS and RAF), lymphoid leukemias (JAK2 fusion protein, TIE-1, CDK modulators), lymphoma (ALK, CDK modulators, mTOR), myeloproliferative disorders (PDGF-R or FGF-R fusion gene products, FGF-R1) and myeloma (FGF-R3, STAT3). Over the past five years, the number of kinase-targeted drug therapies undergoing clinical development has increased exponentially. This review will focus on novel kinase targets currently undergoing preclinical and clinical investigation.
Curr Mol Med 2005 Nov
PMID:Kinases as drug discovery targets in hematologic malignancies. 1630 89

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.
Curr Mol Med 2005 Nov
PMID:Mammalian target of rapamycin as a therapeutic target in leukemia. 1630 91

Mice transgenic for the R4A-Cmu heavy chain of an anti-dsDNA antibody, maintain tolerance by anergy and deletion. In C57BL/6 mice overexpressing CD19, a molecule, which lowers the threshold for B cell activation, elevated levels of serum autoantibodies have been observed. In the present study, we wished to determine whether CD19 overexpression could alter the induction of tolerance in R4A-Cmu mice and lead to the secretion of transgenic anti-dsDNA antibodies. We, therefore, bred R4A-Cmu transgenic mice-to-mice transgenic for human CD19 (hCD19) and generated R4A-Cmu mice heterozygous and homozygous for hCD19. We, now report the spontaneous secretion of transgenic IgM anti-dsDNA antibody in the sera of R4A-Cmu mice overexpressing CD19, indicative of a loss of B cell tolerance. We observe that transgenic B cells secreting anti-dsDNA antibody in these mice are T independent and display a marginal zone like phenotype althought they do not reside in the MZ. In addition, they appear to be derived from the conventional B2 subset rather than the B1 subset. Interestingly, a subset of the anti-dsDNA B cells in these mice still display the phenotype and functional characteristics of anergic B cells. These B cells cannot be activated to secrete antibody following BCR crosslinking, however, they are hyper-responsive to activation by innate signaling mechanisms. This suggests that CD19 overexpression may promote anergic B cells to escape tolerance by converging with BCR independent pathways, thereby rendering these B cells hyper-responsive to innate signaling.
Mol Immunol 2006 Apr
PMID:Loss of tolerance of anti-dsDNA B cells in mice overexpressing CD19. 1643 Sep 62

Chronic myeloid leukemia (CML) originates from the hematopoietic stem cell and is characterized by the reciprocal translocation t(9;22)(q34;q11), which results in the BCR-ABL fusion gene on chromosome 22q-, also known as the Philadelphia chromosome. This chimeric gene codes for a cytoplasmic protein with constitutive tyrosine-kinase activity, responsible for cellular transformation and leukemogenesis in CML. The aim of this observational cohort study was to discriminate and quantify BCR-ABL transcripts in the peripheral blood of patients with CML who were treated with imatinib mesylate (Glivec, Novartis). Twenty-two patients were followed for six months during treatment. Quantitative real time polymerase chain reaction was performed before treatment and after 3 and 6 months from treatment initiation. As compared with the third month, there was a significant decrease in BCR-ABL expression in the sixth month of treatment (P = 0.0002). At the sixth month, there was a significant difference in the levels of the two major transcripts of BCR-ABL, B2A2 and B3A2 (P = 0.0347), indicating that B2A2 may be more sensitive to imatinib. The results of our study indicate that imatinib is able to modify the natural history of CML, and raise the hypothesis that patients who express the B2A2 transcript may have a better prognosis.
Genet Mol Res 2005 Dec 30
PMID:Differential molecular response of the transcripts B2A2 and B3A2 to imatinib mesylate in chronic myeloid leukemia. 1647 28

B-1 cells constitute a unique B cell subset that differs phenotypically, biochemically, and functionally from the predominant population of conventional B-2 cells. Functional differences include constitutive secretion of natural immunoglobulin and failure of BCR signaling to initiate proliferation. The origin of these differences remains uncertain. We hypothesized that unbiased analysis of differences in protein expression between highly pure populations of B-1 and B-2 cells might provide information not readily available through other means. To pursue this, we undertook 2D gel analysis of B-1 and B-2 cells combined with mass spectrometry. We identified the smooth muscle protein, transgelin 2, in peritoneal (but not splenic) B-1 cells and did not find it in splenic B-2 cells; these results were confirmed by Western blot analysis, which showed a more than 60-fold difference in transgelin 2 expression between peritoneal B-1 and splenic B-2 cells. In contrast, levels of transgelin 2 RNA differed to a much lesser extent (3-fold) in the two B cell populations, so transgelin 2 is an example of a molecule whose subset-specific expression is more readily detected by proteomic than transcriptomic analyses. Finally, transgelin 2 protein expression was induced in splenic B-2 cells; thus, transgelin 2 joins a number of other inducible molecules that are constitutively expressed by peritoneal B-1 but not splenic B-2 cells. Although the role of transgelin 2 in B-1 cell function remains uncertain, identification of this molecule demonstrates the value of examining protein expression in this B cell subset.
Mol Immunol 2006 May
PMID:B-1 cells express transgelin 2: unexpected lymphocyte expression of a smooth muscle protein identified by proteomic analysis of peritoneal B-1 cells. 1648 89

Real-time quantitative reverse-transcription polymerase chain reaction (RQ-PCR) methods for the quantitation of BCR-ABL mRNA in the blood of patients with chronic myeloid leukemia (CML) has become the predominant molecular monitoring technique. The BCR-ABL fusion gene is expressed in over 95% of patients with CML, and RQ-PCR provides a reliable, high-throughput method to accurately assess the level of treatment response and provides an early indication of emerging drug resistance. The ABI Prism 7700 Sequence Detection System uses TaqMan fluorogenic probes to quantitate specific nucleic acid sequences using RQ-PCR. The analyzer monitors an increase in fluorescence during the PCR cycle, which is proportional to the amount of accumulated product. The starting copy number is calculated relative to a series of standards. The copy number is normalized to a control gene that compensates for variations in the efficiency of the RT step and for the degree of RNA degradation. In our experience, reliable and consistent RQ-PCR requires thorough validation of all aspects of the procedure, including the selection of an appropriate control gene, careful assay design to avoid polymorphisms in primer or probe binding sites and to exclude the amplification of contaminating DNA, and monitoring the performance of the RQ-PCR by the use of quality control samples.
Methods Mol Med 2006
PMID:Diagnosis and monitoring of chronic myeloid leukemia by qualitative and quantitative RT-PCR. 1650 78

The major mechanism of imatinib resistance for patients with chronic myeloid leukemia (CML) is clonal expansion of leukemic cells with mutations in the Bcr-Abl fusion tyrosine kinase that reduce the capacity of imatinib to inhibit kinase activity. The early detection of such mutations may allow timely treatment intervention to prevent or overcome resistance. Direct sequencing of the BCR-ABL kinase domain is relatively rapid and allows detection of emerging mutations at a sensitivity of approx 20%. Mutations have been detected over a range of 242 amino acids, which spans the entire kinase domain. For optimal sensitivity, the kinase domain of the abnormal gene should be isolated by reverse-transcription (RT) polymerase chain reaction (PCR) amplification using primers that hybridize to the BCR and ABL genes. The quality of the RNA is assessed by real-time quantitative PCR prior to analysis, and BCR-ABL levels are determined. Only RNA of adequate quality is used to ensure accurate and reproducible mutation analysis. Depending on the level of BCR-ABL transcripts, a one- or two-step PCR is required to amplify the kinase domain. Direct sequencing with dye terminator chemistry is performed using PCR-purified products. The sequence is compared to an ABL kinase domain reference sequence using sequencing analysis software, which aligns the sequences and highlights single or multiple mutations.
Methods Mol Med 2006
PMID:Detection of BCR-ABL mutations and resistance to imatinib mesylate. 1650 79


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