Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported the establishment of an interleukin-3 (IL-3)-dependent and phenotypically myeloid cell line (TALL-103/3), obtained by culturing cells from an immature T-lymphoblastic leukemia in the presence of IL-3. These cells differentiated into a T-lymphoid cell line (TALL-103/2) upon removal of IL-3 and incubation in IL-2. Despite the different phenotype, the two cell lines remained karyotypically and genotypically identical. Here, we have analyzed the phenotypic changes and the signaling events induced by these two lymphokines in TALL-103/3 cells by switching them to temporary growth in IL-2 and returning them to IL-3. All four sublines obtained (the myeloid in IL-3 and the lymphoid in IL-2) expressed RNA for CD3, IL-2 receptor (R) alpha, and T-cell receptor (TCR)-gamma and -delta chains. However, cells cultured in IL-3 failed to express detectable levels of the IL-2R beta chain at both the protein and RNA levels, whereas cells exposed to IL-2 always expressed IL-2R beta. In parallel with the changes in IL-2R beta expression, the SRC-like protein tyrosine kinase (PTK) p56 LCK could not be detected in IL-3-dependent cells, but was abundant in the IL-2-dependent cells and underwent markedly increased autophosphorylation in response to IL-2. In contrast, p53/p56 LYN was highly expressed in IL-3-dependent cells, and greatly decreased when these cells were switched to growth in IL-2. LYN kinase autophosphorylation modestly increased in response to IL-3. None of the other kinases in the SRC family that were tested underwent increased autophosphorylation after lymphokine stimulation, indicating the specificity of IL-2 for LCK and of IL-3 for LYN. The TALL-103 cell lines provide a unique system to study the interaction between lymphokines and SRC-family PTKs in signal transduction pathways leading to hematopoietic cell differentiation.
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PMID:Phenotypic changes induced by interleukin-2 (IL-2) and IL-3 in an immature T-lymphocytic leukemia are associated with regulated expression of IL-2 receptor beta chain and of protein tyrosine kinases LCK and LYN. 137 47

Recently, interleukin 2 (IL-2) has been shown to induce increased activity of the p56lck protein-tyrosine kinase (PTK) in T-cell and natural killer cell lines, and evidence for a direct interaction between the p75 subunit of the IL-2 receptor (IL-2R) and this src-family kinase has been reported. Though these findings suggest a central role for lck in IL-2 signal transduction, one problem with this idea is that not all IL-2-responsive cells express the lck gene. For this reason, we examined the effects of IL-2 on the activity of src-like kinases in a pro-B cell line, F7, that lacks p56lck but that displays high-affinity IL-2Rs and vigorously proliferates in response to this lymphokine. Of the eight known src-family PTKs, F7 cells were shown to contain only p53/56lyn, p59fyn, and a small amount of p62yes. Stimulation of resting F7 cells with IL-2 induced a rapid (detectable within 1 min and maximal at 15 min) and concentration-dependent increase in the specific activity of p53/56lyn kinase, as assessed by in vitro kinase assays. This effect of IL-2 on p53/56lyn kinase was specific, since no IL-2-inducible changes were detected in the activities of the p59fyn and p62yes kinases. Furthermore, by using a monoclonal antibody specific for the approximately 75-kDa beta subunit of the IL-2R (referred to as p75/IL-2R beta), evidence for physical association between the lyn kinase and the IL-2R complex was obtained, in that a small proportion of the p53/56lyn kinase in F7 cells, but no detectable p59fyn kinase, was coimmunoprecipitated with p75/IL-2R beta. When combined with the recent evidence that IL-2 regulates p56lck in T cells, these results indicate that some flexibility exists in the ability of various src-like PTKs to participate in IL-2 signal transduction mechanisms and raise the possibility that lineage-specific (T-versus B-cell) responses to IL-2 may be determined at least in part by the repertoire of src-like PTKs expressed in the cell.
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PMID:Interleukin 2 regulates the activity of the lyn protein-tyrosine kinase in a B-cell line. 155 73

Sera and cerebrospinal fluid (CSF) from patients with human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM) were analyzed by Western blotting, and normal human leukocytes were transformed by co-cultivation with HAM patients' leukocytes. The sera and CSF from all HAM patients formed specific bands with HTLV-1 viral proteins, including p19, p24, p28, p32, p40 and p53. After 2-3 weeks of co-cultivation, scattered foci of cell aggregates were noted on macrophage sheets. Surface markers of the transformed cells were OKT3(+), OKT4(+), OKT8(-), IL-2 receptor(+) and EBNA(-). Chromosome analysis showed a normal karyotype. HTLV-1 viral genome was integrated into DNA isolated from transformed cell lines. Electron microscopy revealed type C virus particles in transformed T-cell lines. These results indicate that peripheral leukocytes from HAM patients can transform HTLV-1-negative leukocytes and HAM patients have the potential to acquire adult T-cell leukemia in the future.
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PMID:Transformation of human leukocytes by co-cultivation with HTLV-1-associated myelopathy patients' leukocytes. 288 13

Human immunodeficiency virus type 1 (HIV-1) Nef protein causes the loss of cell surface CD4 and interleukin-2 (IL-2) receptor (Tac) from peripheral blood mononuclear cells (PBMC) and CD4+ T-cell lines. As both CD4 and the IL-2 receptor play crucial roles in antigen-driven helper T-cell signalling and T-cell proliferation, respectively, the role of Nef in the viral life cycle may be to perturb signalling pathways emanating from these receptors. However, the intracellular targets for Nef that result in receptor down-regulation are unknown. Using a recombinant glutathione S-transferase-full-length 27 kDa Nef (Nef27) fusion protein, produced in Escherichia coli by translation from the first start codon of HIV-1 nef clone pNL4-3, as an affinity reagent to probe cytoplasmic extracts of MT-2 cells and PBMC, we have shown interaction with at least seven host cell protein species ranging from 24 to 75 kDa. Immunoblotting identified four of these proteins as p56lck, CD4, p53, and p44mapk/erk1, all of which are intimately involved in intracellular signalling. To assess the relevance of these interactions and further define the biochemical activity of Nef in signal transduction pathways, highly purified Nef27 protein was introduced directly into PBMC by electroporation. Nef27-treated PBMC showed reduced proliferative responsiveness to exogenous recombinant IL-2. Normally, stimulation of T-cells by IL-2 or phorbol 12-myristate 13-acetate provokes both augmentation of p56lck activity and corresponding posttranslational modification of p56lck. These changes were also inhibited by treatment of PBMC with Nef, suggesting that Nef interferes with activation of p56lck and as a consequence of signalling via the IL-2 receptor. Further evidence for Nef interfering with cell proliferation was the decreased production of the proto-oncogene c-myb, which is required for cell cycle progression, in Nef-treated MT-2 cells. In contrast to the binding characteristics and biological effects of Nef27, the alternate 25-kDa isoform of Nef (Nef25) produced by translation from the second start codon of HIV nef pNL4-3 (57 nucleotide residues downstream) was shown to interact with only three cellular proteins of approximately 26, 28, and 56 kDa from PBMC and MT-2 cells, one of which was identified as p56lck. Also, proliferation and posttranslational modification of p56lck in response to IL-2 stimulation were not profoundly affected by treatment of PBMC with Nef25 compared with Nef27.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines. 785 25

The binding of interleukin 2 (IL-2) to the IL-2 receptor (IL-2R) induces a rapid increase in tyrosine phosphorylation of cellular proteins. In a previous study, we have shown that p56lck (lck), a src-family protein tyrosine kinase (src-PTK), physically and functionally associates with the IL-2R beta chain (IL-2R beta). To further investigate a role of src-PTKs in IL-2 signaling, we analyzed a mouse pro-B-cell line, in which lck is not expressed detectably. We observed that in this cell line, IL-2 induces activation of at least two src-PTKs, p59fyn (fyn) and p53/56lyn (lyn). Interestingly, stimulation of this cell line with IL-3 also induces activation of src-PTKs. The activation of fyn or lyn seems to be selective for stimulation with IL-2 or IL-3 since stimulation with IL-6 fails to activate them. Furthermore, we provide evidence for the physical association of fyn with IL-2R beta. Taken together with previous results, our current study suggests that different src-PTKs, each of which is expressed in a cell-type-specific manner, can participate in the IL-2 signal transduction.
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PMID:Functional coupling of the src-family protein tyrosine kinases p59fyn and p53/56lyn with the interleukin 2 receptor: implications for redundancy and pleiotropism in cytokine signal transduction. 848 35

Since the initial report of adult T-cell leukemia (ATL) in 1976, a number of investigators have described the basic biologic aspects of this disease. However, the precise mechanism of leukemogenesis remains unclear. Primary ATL cells demonstrate autonomous and IL-2 responsive growth in vitro. The autonomous growth of the cells is thought to be mediated by IL-2 in an autocrine manner, at least in part. These growth activities are related inversely to survival, and may be useful prognostic determinants. The viral Tax protein stimulates IL-2 and IL-2 receptor alpha expression via nuclear transfer factor NF-kappaB induction. We showed that marked activation of the Tax-NF-kappaB pathway is seen only in acute-type ATL patients. Recent studies show that mutations of p16 and p53 are also found in acute and lymphoma-type ATL. These appear to be late events in ATL leukemogenesis. The relationship between activation of Tax-NF-kappaB pathway and mutations of p53 and p16 genes is unknown. A few other genetic events may be involved in earlier stages of the entire process of ATL leukemogenesis, leading to smoldering and chronic-type ATL. These gene mutations may be accumulated by Tax protein during the long process from the time of HTLV-I infection to the onset of ATL.
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PMID:Autonomous and interleukin-2-responsive growth of leukemic cells in adult T-cell leukemia (ATL): a review of the clinical significance and molecular basis of ATL cell growth. 938 55

Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL) transforms human T cells both in vivo and in vitro. However, the long latency period between infection and development of ATL, as well as the small fraction of the infected population that actually develops this disease, suggest that factors in addition to the virus are involved in its pathogenesis. Mutation of tumor suppressor gene p53 has been found in both HTLV-I-transformed T-cell lines and ATL cases at relatively low frequency. However, increasing evidence supports p53 functional impairment in HTLV-I-transformed T cells. Tax, the major transactivator of HTLV-I, is critical for the initial events involved in transformation. We have considered the possibility that p53 may regulate transcription of viral and cellular genes important for viral replication and transformation. Inactivation of p53 function might then permit constitutive expression of these viral and cellular genes. We have investigated the effects of wild-type and mutant p53 on Tax-mediated activation of the HTLV-I long terminal repeat (LTR) and the promoters of several cellular genes including the interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF ), and IL-2 receptor alpha chain gene. Jurkat, HuT78, and U937 cells were cotransfected with plasmids containing a chloramphenicol acetyltransferase (CAT ) reporter gene under viral or cellular promoter control and the Tax expression vector, in addition to vectors for a wild-type or mutant p53. Wild-type p53 is a potent repressor of viral and cellular activation by Tax. Mutations within p53 severely inhibit this downregulation. We also show that wild-type p53 suppresses transcription from the HTLV-I LTR in Jurkat-Tax, a T-cell line stably expressing Tax, and MT-2, a HTLV-I-transformed T-cell line. Wild-type, but not mutant, p53 interfered with the binding of TATA-binding protein (TBP) to the TATA motif of the HTLV-I LTR. These results suggest that p53 inactivation may lead to upregulation of viral and cellular genes and may also be important for establishment of productive viral infection and development of ATL.
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PMID:Repression of transcription from the human T-cell leukemia virus type I long terminal repeat and cellular gene promoters by wild-type p53. 938 10

Several alterations in the mechanism of cell cycle control have been observed in human T-lymphotropic virus type I (HTLV-I)-infected cells. Here, it is reported that HTLV-I-infected cells both in their immortalized and transformed phase do not undergo apoptosis following ionizing radiation (IR) treatment. However, when IL-2 withdrawal is combined with genotoxic stress, HTLV-I-infected T-cells in their immortalized phase (IL-2-dependent) undergo apoptosis where as their transformed counterparts (IL-2-independent) do not. These results suggest that, during the transformation process, the HTLV-I-infected T-cells become less sensitive to cell death signals through the acquisition of constitutive activation of the IL-2 receptor pathway. The expression of bcl-2 and bcl-XL proteins, which are known to increase cell survival mediated by IL-2, as well as of p21waf1 and p53, was not substantially different in immortalized and transformed cells following IR. All together, these findings suggest that activation of alternative anti-apoptotic pathways, regulated by IL-2, might be responsible for the differential cell death response observed in immortalized versus transformed HTLV-I-infected T-cells.
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PMID:Differential response to genotoxic stress in immortalized or transformed human T-lymphotropic virus type I-infected T-cells. 1042 24

HTLV-I is causually related to the oncogenesis of adult T cell leukemia (ATL). However, the precise mechanism of HTLV-I oncogenesis is unclear. HTLV-I Tax protein functions as an activator of various cellular genes, including IL-2, IL-2 receptor-alpha, and c-fos through the activation of nuclear transfer factors such as NF-kappaB and SRF, and also potently activates trascription of viral genes through CREB/ATF sites in the viral LTR. However, Tax activation of HTLV-I infected T cells through the above pathways induces polyclonal proliferation of the cells in vitro; Tax however may function only transiently in the immediate post-infection period following infection in vivo. The long latent period of 60 years from infection to onset of disease suggests other mechanisms for ATL oncogenesis. Recent studies suggest that the malignant transformation of ATL is a multi-hit phenomena, suggesting that discrete genetic events are responsible for ATL oncogenesis. These genetic events could be responsible for the different stages of ATL: smoldering, chronic, lymphoma, and acute type, p16 and p53 genes are important negative regulators of the cell cycle and are often found to be mutated in neoplasms. Recent studies including ours demonstrated a high frequency of alteration of these two genes in primary ATL cells. Furthermore, alteration of the two genes is associated with acute but not chronic type ATL. In addition, p16 gene alteration is linked to the growth rate of ATL cells, suggesting that the alteration of these cell cycle regulatory genes may be related to progression from smoldering or chronic to acute or lymphoma type ATL. Tax may be involved in mutagenesis of these genes through suppression of DNA-beta polymerase gene expression during the process from latent period to acute/lymphoma type. Once transformation occurs, activation of the pathway between Tax and the three nuclear transfer factors, NF-kappaB, SRF, and CREB/ATF, contributes to establish the aggressive manifestations of acute/lymphoma type ATL cells.
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PMID:HTLV-I Tax related dysfunction of cell cycle regulators and oncogenesis of adult T cell leukemia. 1142 48

The chimaeric protein interleukin-2 (IL-2)-Bax was designed to target and kill specific cell populations expressing the IL-2 receptor. However, it is not well understood how IL-2-Bax causes target cells to die. In the present study, we investigated the pathway of apoptosis evoked by IL-2-Bax and the possible involvement of endogenous Bax in this process. We report here that, upon internalization of IL-2-Bax into target cells, it is localized first mainly in the nucleus, and only later is it translocated to the mitochondria. Similarly, endogenous Bax is also partially localized in the nucleus, and accumulates mainly in this compartment soon after physiological triggering of apoptosis. Despite the fact that Bax has no nuclear localization sequence, our data suggest that Bax has one or more physiological roles and/or substrates within the nucleus. Indeed, a dramatic repression of nuclear Tax protein expression was induced following treatment of HUT-102 cells with IL-2-Bax, similar to what occurs following serum deprivation of these cells. Unexpectedly, induction of apoptosis using IL-2-Bax was preceded by enhanced expression of newly synthesized Bax protein and suppression of Bcl-2. This imbalance between the pro- and anti-apoptotic genes was associated with p53 induction, although IL-2-Bax activity was also evident in cells lacking p53 expression. By studying the mechanism of action of IL-2-Bax, we were able to follow the intrinsic events and their cascade that culminates in cell death. We have shown that the ability of IL-2-Bax to affect the intracellular apoptotic machinery within the target cells, and to cause the cells to die, uses a mechanism similar to that induced following a normal apoptotic signal.
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PMID:Mechanism of action of interleukin-2 (IL-2)-Bax, an apoptosis-inducing chimaeric protein targeted against cells expressing the IL-2 receptor. 1240 5


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