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: UNIPROT:A9QXG9 (bcl-2)
7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bcl-2 protein plays a central role in the regulation of programmed cell death in a variety of tissues and is pivotal to the survival of lymphocytes in vivo. The growth factors responsible for survival of normal lymphocytes are unknown but are likely to maintain viability in part through the regulation of bcl-2 expression. A subset of human natural killer (NK) cells (CD3-CD56bright) are unique among lymphocytes in their constitutive expression of c-kit, a tyrosine kinase cell surface receptor that binds c-kit ligand (KL). Alone, KL does not promote proliferation or further differentiation of CD56bright NK cells. We now report that, in the absence of serum or additional growth factors, KL prevents apoptosis of cultured CD56bright NK cells, as assessed by DNA fragmentation studies, and maintains viability, as measured by biologic responses (i.e., proliferation and cytotoxicity) to the subsequent addition of other cytokines. Furthermore, we demonstrate that KL induces CD56bright NK cells to express the bcl-2 protein. In the presence of anti-c-kit antibody, the tyrosine kinase inhibitor genistein, or bcl-2 antisense oligonucleotide, the protective effect of KL on the survival of CD56bright NK cells is dramatically reduced. These data demonstrate that the binding of KL to its tyrosine kinase receptor results in the upregulation of bcl-2, thereby preventing apoptosis in this subset of normal human lymphocytes. As soluble KL is plentiful in normal human serum, this survival mechanism may be operative for CD56bright NK cells in vivo.
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PMID:The c-kit ligand suppresses apoptosis of human natural killer cells through the upregulation of bcl-2. 751 82

Activation of the multicomponent interleukin-2 receptor (IL-2R) complex leads to a rapid increase in tyrosine phosphorylation of a number of cellular proteins including the IL-2R beta and IL-2R gamma chains of the IL-2R and the RAF-1 serine threonine kinase. In addition, phosphatidylinositol 3-kinase (PI-3K) protein and activity can be immunoprecipitated with anti-phosphotyrosine and anti-IL-2R beta antibodies from IL-2-activated but not resting T lymphocytes. We have demonstrated that the SH2 (SRC homology 2) domains of the 85 kDa subunit of PI-3K are sufficient to mediate binding of the PI-3K complex to tyrosine phosphorylated, but not non-phosphorylated IL-2R beta, suggesting that tyrosine phosphorylation is an integral component of the activation of PI-3K by the IL-2R. Since none of the members of the IL-2R complex contains an intrinsic tyrosine kinase domain, IL-2-induced tyrosine phosphorylation must be the consequence of activation of intracellular tyrosine kinases. SRC family members including lck, lyn and fyn have been demonstrated to associate with IL-2R beta through binding of the kinase domain to the acidic domain of IL-2R beta. However, we have demonstrated that the serine rich (SD) region of the cytosolic domain of IL-2R beta is also required for association of a tyrosine kinase with the IL-2R complex and that IL-2 can induce proliferation and tyrosine phosphorylation in cell lines which lack the known SRC family kinases expressed by T lymphocytes. Thus members of other kinase families besides SRC may also be involved in mediating IL-2 signal transduction. Biochemical studies and studies of cells expressing mutant IL-2 receptors indicate that IL-2-induced tyrosine kinase activation initiates a complex signaling cascade. The cascade includes SRC family kinase members such as lck, fyn, and lyn, activation of Raf-1 and PI-3K, and ras, and increased expression of the fos, fra-1, and jun protooncogenes. In addition, ligation of the IL-2R leads to rapid increases in myc expression and more delayed increases in the expression of the cdc2 and cdk2 kinases and the cyclins through a tyrosine phosphorylation independent pathway. Whether other biochemical processes initiated by IL-2R ligation, including activation of the MAP2, p70S6 and p90RSK serine threonine kinases, activation of NF-kappa B, and increased expression of Raf-1, Pim-1, bcl-2, IL-2R alpha and IL-2R beta, are consequences of the IL-2-induced tyrosine kinase cascade remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transmembrane signaling by the interleukin-2 receptor: progress and conundrums. 826 Jun 51

BAG-1 is a Bci-2-binding protein which functions in protection from apoptotic cell death. Here we provide evidence for interleukin-2 (IL-2)-mediated upregulation of BAG-1 expression. In hematopoietic cell line BAF-B03 F7 cells, gene transfer mediated expression of the IL-2R beta c chain is sufficient to confer proliferation and cell survival responses to IL-2. In these IL-2R beta c-expressing cells, BAG-1 mRNA was dramatically induced by IL-2. The IL-2-mediated induction of BAG-1 expression required the activation of tyrosine kinase(s) and was sensitive to rapamycin as the induction of bcl-2 expression was. Analysis of the transfectants which express mutant IL-2R beta c chains or mutant Janus family protein tyrosine kinase Jak3 lacking the kinase domain showed that the IL-2-mediated BAG-1 gene expression required the serinerich region within the IL-2R beta c chain, but Jak3 activation was dispensable. The signaling pathway for BAG-1 gene expression thus highly resembles that for bcl-2 gene expression, strongly suggesting that their induction shares the same signaling pathway. In addition, deletion of the serine-rich region led to loss of IL-2-mediated protection from apoptotic cell death. Taken together, these studies demonstrate that the serine-rich region of the IL-2R beta c chain mediates the coordinated expression of bcl-2 and BAG-1 genes, thereby contributing to suppression of apoptosis.
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PMID:Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine-rich region within IL-2 receptor beta c chain. 894 45

Brutons tyrosine kinase (Btk) deficient xid mice have a diminished primary T cell dependent immune response, resulting in a reduced memory B cell frequency. Boosting at 35 days post primary immunization, however, generates a normal secondary immune response, indicating a functional memory B cell compartment. The longevity of B cell memory appears to depend on both the presence of antigen and expression of cell survival genes such as bcl-2. Since there is a natural decay in the number of memory B cells over time and since xid B cells have been demonstrated to have reduced Bcl-2 levels, we aimed at determining whether B cell memory of xid mice would be long-lasting. This report demonstrates that memory B cell precursors are detectable in xid mice more than 100 days after primary immunization. Furthermore, a secondary immune response of normal magnitude and kinetics can be generated in xid mice at 150 days after primary immunization indicating that B cell memory is long-lived in xid mice. Thus, although survival of B cell memory is presumably dependent on immunoglobulin (Ig)-mediated interaction with antigen, this interaction does not depend solely on signalling through Btk.
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PMID:B cell memory in xid mice is long-lived despite reduced memory B cell frequency. 920 5

Normal human keratinocytes synthesize and release nerve growth factor (NGF) and express both the low- and the high-affinity NGF receptor. Because NGF has been shown to rescue certain cell types from programmed cell death, we investigated the role of endogenous NGF in preventing keratinocyte apoptosis. We report here that apoptosis is induced in normal human keratinocytes in culture by blocking endogenous NGF signaling with either anti-NGF neutralizing antibody or K252, a specific inhibitor of the tyrosine kinase high-affinity NGF receptor. Apoptosis was assessed by DNA laddering, electron microscopy, and in situ nick end labeling technique. In anti-NGF-treated keratinocytes, the apoptotic process starts at 96 h, and is maximal at 120 h. After K252 treatment, apoptosis starts at 48 h and peaks at 120 h. Because the product of the bcl-2 proto-oncogene protects many cell types from apoptosis, we measured the levels of this protein in apoptotic keratinocytes. We found that both K252 and anti-NGF antibody strikingly downregulate bcl-2 expression, starting at 72 h. Furthermore, HaCat keratinocytes stably transfected with a plasmid containing bcl-2 cDNA fail to undergo apoptosis when treated with K252. These findings show that autocrine NGF acts as a survival factor for human keratinocytes in vitro through its high-affinity NGF receptor, possibly by maintaining constant levels of Bcl-2.
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PMID:Autocrine nerve growth factor protects human keratinocytes from apoptosis through its high affinity receptor (TRK): a role for BCL-2. 940 17

The selective and conspicuous absence of a novel receptor-Ck (having affinity for cholesterol moiety in lipoproteins and intrinsic tyrosine kinase activity) in various leukemic cell lines/patients, prompted us to explore the nature of interrelationship between receptor-Ck deficiency and over-expression of genes coding for bcl-2, cyclin 'D', chimeric bcr-abl, c-myc and LDL-receptor in the human promyelocytic leukemic cell line (HL-60). This study revealed unambiguously that deregulated expression of these genes is primarily due to the inability of these cells to express the receptor-Ck gene. Based upon the observations we propose that 'receptor-Ck' deficiency may be responsible for the initiation of chronic myeloid leukemia.
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PMID:Receptor-Ck-dependent regulation of genes in HL-60 cell line. 944 38

Defects of the common gamma chain subunit of the cytokine receptors (gamma c) or of Jak3, a tyrosine kinase required for gamma c signal transduction, result in T-B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (> 3,000/microL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+ HLA-DR+ CD62L(lo)), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in gamma c-/y and in Jak3-/- mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.
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PMID:Development of autologous, oligoclonal, poorly functioning T lymphocytes in a patient with autosomal recessive severe combined immunodeficiency caused by defects of the Jak3 tyrosine kinase. 944 56

Ten years have passed since the molecular cloning of interleukin 6 (IL-6) in 1986. IL-6 is a typical cytokine, exhibiting functional pleiotropy and redundancy. IL-6 is involved in the immune response, inflammation, and hematopoiesis. The IL-6 receptor consists of an IL-6 binding alpha chain and a signal transducer, gp130, which is shared among the receptors for the IL-6 related cytokine subfamily. The sharing of a receptor subunit is a general feature of cytokine receptors and provides the molecular basis for the functional redundancy of cytokines. JAK tyrosine kinase is a key molecule that can initiate multiple signal-transduction pathways by inducing the tyrosine-phosphorylation of the cytokine receptor, gp130 in the case of IL-6, on which several signaling molecules are recruited, including STAT, a signal transducer and activator of transcription, and SHP-2, which links to the Ras-MAP kinase pathway. JAK can also directly activate signaling molecules such as STAT and Tec. These multiple signal-transduction pathways intimately regulate the expression of several genes including c-myc, c-myb, junB, IRF1, egr-1, and bcl-2, leading to the induction of cell growth, differentiation, and survival. The deregulated expression of IL-6 and its receptor is involved in a variety of diseases.
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PMID:Interleukin 6 and its receptor: ten years later. 950 91

Activation of the interleukin-3 (IL-3) receptor is required for the induction of cell proliferation and suppression of apoptosis in primitive hematopoietic progenitor cells. A rapid activation of tyrosine kinases and a phosphatidylcholine-specific phospholipase C has been observed in these cells in response to IL-3. The signal transduction cascades regulating cell proliferation and the suppression of apoptosis are poorly understood. Using human IL-3-dependent TF-1 cells, we have found that the tyrosine kinase inhibitor genistein blocks both the IL-3 suppression of apoptosis and the expression of the cell survival gene bcl-2. In addition, we have found that D609, a specific inhibitor of phosphatidylcholine-specific phospholipase C, also inhibits IL-3-induced expression of the bcl-2 gene without affecting IL-3-induced tyrosine phosphorylation. D609 also drove these cells into apoptosis even in the presence of IL-3. Significantly, genistein inhibited the IL-3 induction of both bcl-2 and c-myc gene. The latter gene is related to the induction of cell proliferation. D609, however, blocked the induction only of the cell survival gene bcl-2. Thus, phosphatidylcholine hydrolysis appears linked to the induction of genes related to cell survival. These data fit with the hypothesis that there is a bifurcation in the signaling pathways downstream of IL-3 receptor-induced tyrosine phosphorylation.
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PMID:A phosphatidylcholine phospholipase C inhibitor, D609, blocks interleukin-3 (IL-3)-induced bcl-2 expression but not c-myc expression in human IL-3-dependent cells. 959 95

The phenotype of hematopoietic cells transformed by the BCR/ABL oncoprotein of the Philadelphia chromosome is characterized by growth factor-independent proliferation, reduced susceptibility to apoptosis, and altered adhesion and motility. The mechanisms underlying this phenotype are not fully understood, but there is evidence that some of the properties of BCR/ABL-expressing cells are dependent on the activation of downstream effector molecules such as RAS, PI-3k, and bcl-2. We show here that the small GTP-binding protein Rac is activated by BCR/ABL in a tyrosine kinase-dependent manner. Upon transfection with a vector carrying the dominant-negative N17Rac, BCR/ABL-expressing myeloid precursor 32Dcl3 cells retained the resistance to growth factor deprivation-induced apoptosis but showed a decrease in proliferative potential in the absence of interleukin-3 (IL-3) and markedly reduced invasive properties. Moreover, compared with BCR/ABL-expressing cells, fewer BCR/ABL plus N17Rac double transfectants were capable of homing to bone marrow and spleen. Consistent with these findings, survival of SCID mice injected with the BCR/ABL plus N17Rac double transfectants was markedly prolonged as compared with that of mice injected with BCR/ABL-expressing cells. Together, these data support the important role of a Rac-dependent pathway(s) controlling motility in BCR/ABL-mediated leukemogenesis.
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PMID:BCR/ABL-mediated leukemogenesis requires the activity of the small GTP-binding protein Rac. 975 55


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