Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 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 we described the establishment in culture and the immunophenotypic and functional characteristics of a human T-leukemia line TALL-103/2 derived from the T-cell receptor (TCR)-gamma/delta subset of T-lymphocytes. TALL-103/2 cells are absolutely dependent on interleukin 2 (IL-2) for their growth and survival in culture and thus provide a model cell line for studies of IL-2 signal transduction in a TCR-gamma/delta T-cell. In this report, we focus on the regulation of SRC-family protein tyrosine kinases (PTKs) by IL-2. TALL-103/2 cells were found to contain p56-LCK, p59-FYN, p62-YES and p53/56-LYN. Stimulation of growth factor-deprived TALL-103/2 cells with IL-2, however, induced increases in the relative activity only of the p56-LCK kinase. This IL-2-mediated increase in LCK kinase activity was manifested both by increased kinase autophosphorylation and by increased phosphorylation of the exogenous substrate enolase during in vitro kinase assays. Furthermore, immunoblot assays determined that the levels of p56-LCK protein were unaltered by IL-2-treatment, indicating that the measured elevations in LCK kinase activity reflected an increase in the specific activity of this PTK. In TALL-103/2 cells, IL-2 stimulated concentration-dependent increases in p56-LCK activity that displayed rapid and transient kinetics: detectable increases occurred within 1 minute after IL-2 stimulation, peaked at 10 minutes, and declined to baseline levels by 30 minutes. Treatment of TALL-103/2 cells with IL-4 abrogated IL-2-initiated proliferation, but did not inhibit IL-2-mediated activation of p56-LCK.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin 4 inhibits IL-2-induced proliferation of a human T-leukemia cell line without interfering with p56-LCK kinase activation. 142 Sep 98

Unlike many other growth factor receptors, the known subunits of the receptors for the Interleukins IL-2 and IL-3 lack intrinsic tyrosine kinase activity, and yet increases in the phosphorylation of proteins on tyrosines is a rapid event in hematolymphoid cells following stimulation with these lymphokines. Here we show that IL-2 and IL-3 regulate the activity of specific members of the SRC-family of non-receptor protein tyrosine kinases (PTKs). In IL-2-dependent T-cell lines, IL-2 induced rapid and transient increases in the activity of the p56-LCK kinase without influencing the activities of other SRC-like PTKs (p59-FYN, p62-YES) in these T-lymphocytes. In contrast to IL-2's effects on p56-LCK in T-cells, studies of an IL-2-responsive cell line of the B-cell lineage that lacks p56-LCK revealed that IL-2 specifically regulates the activity of the p53/56-LYN kinase. Thus, some flexibility exists in the ability of various SRC-like PTKs to functionally couple to IL-2 signalling pathways. In several IL-3-dependent myeloid-committed leukemic cell lines, IL-3 was found to specifically regulate the activity of the p53/56-LYN kinase without affecting the activities of other SRC-like PTKs (p59/64-HCK, p59-FYN, p62-YES) in these hematopoietic cells. This finding that p53/56-LYN can be regulated by both IL-2 in B-lineage cells and IL-3 in myeloid-committed cells demonstrates that the same SRC-family PTK can participate in signal transduction events mediated via two independent receptor systems. Taken together, our findings imply that the specific combinations of lymphokine receptors and SRC-like PTKs available for coupling with those receptors are coordinately controlled during the differentiation of hematopoietic cells.
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PMID:Regulation of SRC-family protein tyrosine kinases by interleukins, IL-2, and IL-3. 160 36

Chronically immunosuppressed individuals are susceptible to lymphoreticular tumors. Up to 15% of patients with congenital deficiencies such as ataxia=telangiectasia may develop malignancies, mainly high-grade B cell non=Hodgkin's lymphomas (NHLs). AIDS lymphomas are comprised of NHLs including Burkitt's lymphoma (BL) and primary cerebral lymphomas (PCLs). Almost 3% of all AIDS patients (2824 of 97,258 cases) developed NHL. Epstein-Barr virus (EBV) as a co-factor in AIDS lymphomagenesis has been studied: in 12 cases of 24 AIDS lymphomas EBV by DNA in situ hybridization was found. In an analysis of 6 primary cerebral lymphomas, .5 were positive for EBV DNA by Southern blotting. In Burkitt's lymphoma the characteristic genetic alteration affects the c-myc oncogene. In 1/3 of BL p53 mutations were found but none in the 43 NHLs suggesting that p53 mutations and c-myc activation act synergistically in the pathogenesis of these tumors. Cytotoxic agents dideoxyinosine, dideoxycytosine, and zidovudine may cause secondary neoplasia. 8 of 55 AIDS patients under zidovudine treatment developed high-grade lymphoma 23.8 months subsequently; recently doses were reduced. PCL was found in 21 of 90 patients. A 5.2 months survival was associated with combined treatment with cyclophosphamide, Oncovin (vincristine), methotrexate, etoposide, and cytosine arabinoside compared with 11.3 months with chemotherapy. Colony-stimulating factors (CSFs) alleviate drug-induced myelotoxicity and zidovudine-induced neutropenia, however, l8 of 11 patients receiving granulocyte-macrophage CSF developed hematological toxicity. Interleukine-2 produced by T-helper cells enhancing tumor cells cytotoxicity has been used in AIDS-associated cryptosporidial diarrhea and in 4 patients with AIDS lymphoma with modest response, but its stimulation of the HIV-infected substrate may increase viral proliferation.
Int J STD AIDS
PMID:AIDS lymphomas. 161 63

The lymphokine interleukin-3 (IL-3) promotes the growth and survival of immature hematopoietic cells. Previous studies have shown that IL-3 induces rapid increases in protein-tyrosine kinase (PTK) activity in IL-3--dependent cells. Unlike some other hematopoietic growth factor receptors (eg, c-fms and c-kit), however, the known subunits of the IL-3 receptor (IL-3R) lack intrinsic kinase activity. Recently, it was reported that the IL-2R (whose p75 beta-subunit shares sequence homology with a known murine IL-3R subunit and a common beta-subunit of the human IL-3R and granulocyte-macrophage colony-stimulating factor [GM-CSF] receptors) can physically associate with and regulate the activity of the SRC-family PTK, p56-LCK. Because most IL-3--dependent cells contain p53/56-LYN, but not p56-LCK, we explored the effects of IL-3 on the activities of LYN and other SRC-like PTKs in two human leukemic cell lines, AML-193 and TALL-101, which are phenotypically myeloid, and whose in vitro growth is dependent on IL-3. These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck. When these factor-dependent leukemic cell lines were deprived of lymphokine to achieve cellular quiescence and then restimulated with IL-3, rapid increases (detectable within 1 minute and maximal by 10 minutes) were observed in the activity of the p53/56-LYN kinase, as assessed by in vitro kinase assays. In contrast, no alteration in the activities of other SRC-family PTKs present in these cells was detected after restimulation with IL-3 under the same conditions. This effect of IL-3 reflected an increase in the specific activity of the LYN kinase, because levels of the 53-Kd and 56-Kd LYN proteins were unaltered by IL-3 stimulation, as assessed by immunoblotting. Furthermore, the magnitude of these inducible increases in LYN kinase activity was dependent on the concentration of IL-3, and correlated with IL-3--induced proliferation. The IL-3--induced upregulation of LYN kinase activity may be mediated by the 120-Kd common subunit of the human IL-3 and GM-CSF receptors, because GM-CSF also stimulated marked increases in the activity of the LYN kinase, whereas granulocyte-CSF (G-CSF) did not, despite inducing cellular proliferation. These observations provide the first example of an IL-3--regulable PTK, and strongly suggest that the p53/56-LYN kinase participates in early IL-3--initiated signalling events, at least in some human leukemic cell lines.
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PMID:Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. 163 19

Oncogene dosage and expression were studied in 16 testicular neoplasms, 14 of germ cell and two of non-germ cell origin. In comparison with normal DNA, tumour DNA of a total of eight patients (seven with germ cell neoplasm and one with testicular lymphoma) showed increased dosages of KRAS2, PDGFA, EGFR, MET and PDGFB. The most frequent (occurring in six tumours) and prominent (up to 3-4-fold) increases were detected in the dosages of KRAS2 (on chromosome 12p) and PDGFA (chromosome 7p), relative to a reference locus from chromosome 2. Importantly, there was a similar increase in 12p dosage in general in these tumours, suggesting the presence of the characteristic isochromosome 12p marker. On the contrary, possible 7p polysomy (assessed by molecular methods) did not explain the PDGFA (or EGFR) changes in all cases. NRAS, MYCN, CSFIR, MYB, MYC, ABL, HRASI, TP53, and ERBB2 did not reveal any consistent alterations in tumour DNA. In RNA dot blot assays the expression of KRAS2, PDGFA, EGFR, or MYC was generally not increased in the tumour samples when compared to that in normal testicular tissue of the same patients although there was interindividual variation in mRNA levels. It thus appears that while oncogene dosage changes occur in a proportion of testis cancers, they are often part of changes in large chromosomal regions or whole arms and are seldom accompanied by altered expression.
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PMID:Oncogenes in human testicular cancer: DNA and RNA studies. 182 52

Chronic myelogenous leukemia (CML) is the best understood human cancer. The molecular basis of CML involves activation of a cellular proto-oncogene--ABL. The consequence is to increase tyrosine kinase activity. This results in a marked clonal increase in the myeloid mass. Later on, cellular maturation is blocked and the decrease eventuates in acute leukemia. Abnormalities of other proto-oncogenes or antioncogenes, like P53, may be involved in leukemia progression. Treatment of CML involves chemotherapy and, more recently, interferon. Whether this treatment prolongs survival or increases the likelihood of cure is unknown but either result seems unlikely. Bone marrow transplants which cure about 50% of persons with CML are most effective when performed in chronic phase.
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PMID:Chronic myelogenous leukemia: molecule to man. 189 3

Chronic myelogenous leukemia (CML) is characterized cytogenetically by the presence of the Philadelphia chromosome, which is the result of a reciprocal translocation between chromosomes 9 and 22. Analysis of the rearranged chromosome 22 have demonstrated that the DNA breakpoints fall within a 5.8-kilobase (kb) region termed M-bcr. In Ph1-acute lymphocytic leukemia, approximately half of the patients have a breakpoint within M-bcr, whereas the remaining half have the break within the first intron of the BCR gene (m-bcr). We have investigated five cases with CML in the blastic phase to search the molecular mechanism of blastic crisis in CML. Using a method of reverse transcriptase-polymerase chain reaction (RT-PCR), we have identified both types of breakpoints in samples of the three cases, suggesting the existence of M-bcr/ABL and m-bcr/ABL chimeric mRNAs in the RNA samples derived from blasts of the three cases. We have further analysed for alterations in the p53 gene in those cases. The p53 gene is now considered to be a tumor suppressor gene and its mutations play a role in the development of many human malignancies. We have attempted to determine whether the p53 gene is involved in the mechanism of blastic crisis in CML. Using the methods of RT-PCR and single stand-conformational polymorphism (SSCP), we have detected expression of only a mutated p53 allele in a case with CML blastic crisis, indicating that inactivation of the p53 gene in both alleles may contribute to the blastic crisis in this case. Accumulation of molecular analysis in more cases will clarify the mechanism of blastic crisis in CML.
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PMID:[Analysis of Ph1-positive leukemia by PCR]. 206 73

The BCR gene (Groffen et al., 1984) plays a critical role in the pathogenesis of human leukemias that involve the Philadelphia chromosome (Ph1) (Rowley, 1973; Nowell & Hungerford, 1960). Cells containing the Ph1 contain a chimeric gene formed from the fusion of BCR (Collins et al., 1987; Lifshitz et al. 1988) and ABL genes that results from the reciprocal translocation of segments of chromosomes 9 and 22 (Shtivelman et al., 1985). The product of this chimera is a 210 kDa protein, termed P210 BCR-ABL, that possesses an activated tyrosine kinase activity (Konopka et al., 1984; Kloetzer et al., 1985). Studies using long-term marrow culture systems and retrovirus-mediated gene transfer have documented that P210 BCR-ABL can stimulate the growth of immature hematopoietic precursor cell types (McLaughlin et al., 1987; Young & Witte, 1984). We have previously reported that P210 BCR-ABL exists in cytoplasmic complexes in association with a 53 kDa protein termed ph-P53 (Maxwell et al., 1987; Li et al. 1988). Similarly, BCR proteins have been found in cytoplasmic complexes containing ph-P53 in cells lacking the Ph1 (Li et al., 1989). These BCR protein complexes possess an associated ser/thr protein kinase activity. In this same study, we found that P210-containing complexes phosphorylate BCR proteins on tyrosine residues in vitro (Li et al., 1989). We now present results which demonstrate that P210 BCR-ABL is tightly associated with P160 BCR and ph-P53 proteins in cytoplasmic complexes from cells containing the Ph1.
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PMID:P210 BCR-ABL is complexed to P160 BCR and ph-P53 proteins in K562 cells. 214 May 98

A critical determinant of the efficacy of antineoplastic therapy is the response of malignant cells to DNA damage induced by anticancer agents. The p53 tumor-suppressor gene is a critical component of two distinct cellular responses to DNA damage, the induction of a reversible arrest at the G1/S cell cycle checkpoint, and the activation of apoptosis, a genetic program of autonomous cell death. Expression of the BCR-ABL chimeric gene produced by a balanced translocation in chronic myeloid leukemia, confers resistance to multiple genotoxic anticancer agents. BCR-ABL expression inhibits the apoptotic response to DNA damage without altering either the p53-dependent WAF1/CIP1-mediated G1 arrest or DNA repair. BCR-ABL-mediated inhibition of DNA damage-induced apoptosis is associated with a prolongation of cell cycle arrest at the G2/M restriction point; the delay of G2/M transition may allow time to repair and complete DNA replication and chromosomal segregation, thereby preventing a mitotic catastrophe. The inherent resistance of human cancers to genotoxic agents may result not only by the loss or inactivation of the wild-type p53 gene, but also by genetic alterations such as BCR-ABL that can delay G2/M transition after DNA damage.
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PMID:BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. 762 Jan 67


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