Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of H-2 antigenic specificities on K36, a spontaneous leukaemia originating from AKR (H-2k) mice, was studied by serology and immunochemistry. Two ascites lines of the tumour, as well as a tissue culture adjusted and cloned tumour line, were used in these studies with similar results being obtained. K36 expresses on its cell surface D-region encoded H-2K antigens but does not express K-region encoded H-2K alloantigens. It also expresses on its cell membrane, H-2 specificities of foreign haplotypes not present on normal AKR lymphoid cells. The molecular basis of the H-2Dd specificity on K36 (H-2k) was analysed by immunoprecipitation and polyacrylamide gel electrophoresis. The specificity was shown to be present on a glycoprotein of apparent molecular weight 45,000. However, antisera against the H-2Dd private specificity (H-2.4) precipitate additional glycoprotein of 45,000D and also 70,000D. In tryptic peptide maps of the isolated 45,000D fraction precipitated by anti-H-2.4 serum from radiolabelled K36 glycoprotein, all H-2Dd specific peptides were present in the same quantitative ratio. This is consistent with the structural identity of the foreign H-2Dd from the K36 tumour with normal H-2Dd and supports the hypothesis of a regulator system controlling the H-2 allelism. Under certain circumstances such a system could cause suppression of one and derepression of the other H-2 gene products.
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PMID:Serological and immunochemical studies of H-2 allospecificities on K36, a syngeneic tumour of AKR. 615 51

Major histocompatibility complex (MHC) class I molecules can function as specific target antigens in T-cell-mediated cytotoxity. In addition, T cells can kill target cells through non-MHC antigens, for example, virally infected cells, if the target and effector cells express the same MHC class I antigens. Consequently, quantitative and/or qualitative variations in the expression of the H-2/HLA antigens on the target cells could interfere with MHC-restricted immune reactions. We have reported that the AKR leukaemia cell line K36.16, a subline of K36 (ref. 3), on which the H-2Kk antigen cannot be detected, is resistant to T-cell lysis and grows very easily in AKR mice. Other AKR tumour cell lines, like 369, which have a relatively large amount of H-2Kk on their surface, are easily killed by T cells in vitro and require a much larger inoculum to grow in vivo. Monoclonal antibodies against H-2Kk, but not against H-2Dk, prevented the killing by T cells. This suggests that some tumour cells grow in vivo because tumour-associated antigen(s) cannot be recognized efficiently by the host's immune system, due to the absence of MHC molecules which would function as restriction elements for T-cell cytotoxicity. We have tested this hypothesis by introducing the H-2Kk gene into the H-2Kk-deficient AKR tumour cell line K36.16 and have now demonstrated directly the biological relevance of H-2Kk antigen expression in the regulation of the in vivo growth of this tumour cell line.
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PMID:Rejection of transplantable AKR leukaemia cells following MHC DNA-mediated cell transformation. 633 39

The transcriptional activation of the major histocompatibility complex (MHC) class I genes by both type I (alpha/beta) and II (gamma) interferons (IFNs) has been extensively studied, and it has been shown that the upregulation of several DNA-binding proteins is critical for this process. In our laboratory, we introduced the mouse H-2Kb gene into the AKR mouse leukaemia cell line K36.16 to effect the generation of tumor-specific immunity. Individual clones were selected and studied. Whereas the MHC class I genes in most of the clones obtained could be stimulated by interferons, one of the clones obtained, clone Kb-S27, failed to be induced, or was at best poorly induced by IFN-alpha/beta and -gamma. Both the exogenous H-2Kb and the endogenous H-2Dk genes behaved in the same manner and were not stimulated by IFNs. The lack of response to IFNs by clone Kb-S27 also resulted in its resistance to the antiproliferative effects of IFNs. This lack of IFN-induction by clone Kb-S27 was not simply due to a change in its surface interferon receptors. Gel-retardation assay and northern blot analysis both demonstrated the lack of induction of the IRF-1 DNA-binding factor in clone Kb-S27. In addition, northern blot analysis showed that the IRF-2 gene expression in clone Kb-S27 was upregulated when compared with the other IFN-inducible clones.
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PMID:Characterization of a novel IRF-1-deficient mutant cell line. 750 33

Non-steroidal antiestrogens such as tamoxifen are known to exert cytotoxic effects against various cell lines in culture. When the antiestrogens are present at sufficiently high concentrations, their cytotoxicity cannot be reversed by estrogens and is demonstrable even with cell lines which lack the estrogen receptor. The mechanism of this cytotoxicity, which is clearly independent of estrogen antagonism, remains unknown. Using two murine cancer cell lines (the K36 leukemia and the EL4 lymphoma cell line), the human breast cancer cell line MCF7, and two non-steroidal antiestrogens (tamoxifen and clomiphene), our laboratory attempted to determine whether the cytotoxic action of non-steroidal antiestrogens was mediated by a mechanism requiring protein or RNA synthesis. In the case of K36 and EL4 cells, inclusion of tamoxifen or clomiphene in the culture medium regularly caused the viable call count to fall below 20-30% of control in 36-48 h. Under these conditions, the addition of inhibitors of protein or RNA synthesis consistently increased viable cell count in a dose-dependent manner. With cultures of K36 cells grown in the presence of 10 microM tamoxifen, for example, the addition of appropriate concentrations of emetine, cycloheximide, puromycin, or actinomycin D increased the percentage of viable cells to 5.0, 2.4, 4.0, and 4.0 times that of control, respectively. Additional experiments revealed that the macromolecular synthesis inhibitors, while effective in inhibiting protein or RNA synthesis to varying degrees, did not affect the cellular uptake of [3H]tamoxifen, suggesting that their ability to protect cells against antiestrogen-induced cell death was not due to an inhibition of cellular uptake of antiestrogens. In the case of MCF7 cells, however, inhibition of protein synthesis did not protect the cells against the cytotoxic effect of tamoxifen. These observations suggest that non-steroidal antiestrogens may exert their cytotoxic effect by at least two different mechanisms; only one of these require de novo protein synthesis. The effect of antiestrogens on K36 and EL4 cells may provide a useful system for the identification of proteins involved in cell death.
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PMID:Inhibitors of protein and RNA synthesis block the cytotoxic effects of non-steroidal antiestrogens. 753 76

The monoclonal antibody C215 (IgG2a) was obtained by the immunization of BALB/c mice with the human colon adenocarcinoma cell line COLO 205 and used in the targeting of colorectal carcinomas. The partial characterization and purification of the C215 target molecule from solubilized COLO 205 membranes indicated that it is an integral membrane glycoprotein of the non-mucin type. The denatured antigen appeared as a major 40-kDa form in Western blots after SDS-polyacrylamide gel electrophoresis and migrated as a monomeric 36-kDa species after the reductive cleavage of intramolecular disulfide bridges. Using a five-step procedure, the antigen was purified 4,300-fold from COLO 205 tumors raised in nude mice to a homogeneity of 95% when assessed by capillary electrophoresis. Removal of N-linked carbohydrate by peptide:N-glycosidase treatment did not affect the visualization of the purified antigen in immunoblots but resulted in a faster migration in the SDS gels. The amino acid sequence was partially determined. Seventeen contiguous NH2-terminal amino acids were identified and coincided exactly with residues 82-98 of the GA733-2 protein cloned by Szala et al. (Szala, S., Froehlich, M., Scollon, M., Kasai, Y., Steplewske, Z., Koprowski, H., and Linnenback, A. J. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3542-3546). Therefore, the predicted amino acid sequence of this protein was used to prepare overlapping synthetic peptides that cover the entire extracellular domain in order to identify the C215 epitope. A likely epitope, close to the NH2 terminus and corresponding to the first distinct hydrophilic stretch after the putative signal sequence, was identified in a peptide enzyme-linked immunosorbent assay. Moreover, GA733-2 cDNA was used for the cloning of the C215 protein from COLO 205 cells and the subsequent transfection to K36.16 mouse T cell leukemia cells. The transfected cells were C215 reactive in fluorescence-activated cell sorter analysis, and a 42 kDa band was visualized in Western blots under both non-reducing and reducing conditions. Our findings indicate a close relationship between the C215 antigen and other members of the GA-733 family, some of which are currently being used as targets in clinical trials with monoclonal antibodies. The mammalian expression system described here will enable further studies into the biological role of this protein and the construction of animal models in order to develop optimal therapeutic strategies.
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PMID:Isolation, partial characterization, and molecular cloning of a human colon adenocarcinoma cell-surface glycoprotein recognized by the C215 mouse monoclonal antibody. 769 97

In yeast, methylation of histone H3 on lysine 36 (H3-K36) is catalyzed by the NSD1 leukemia oncoprotein homolog Set2. The histone deacetylase complex Rpd3S is recruited to chromatin via binding of the chromodomain protein Eaf3 to methylated H3-K36 to prevent erroneous transcription initiation. Here we identify a distinct function for H3-K36 methylation. We used random mutagenesis of histones H3 and H4 followed by a reporter-based screen to identify residues necessary to prevent the ectopic spread of silencing from the silent mating-type locus HMRa into flanking euchromatin. Mutations in H3-K36 or deletion of SET2 caused ectopic silencing of a heterochromatin-adjacent reporter. Transcriptional profiling revealed that telomere-proximal genes are enriched for those that display decreased expression in a set2Delta strain. Deletion of SIR4 rescued the expression defect of 26 of 37 telomere-proximal genes with reduced expression in set2Delta cells, implying that H3-K36 methylation prevents the spread of telomeric silencing. Indeed, Sir3 spreads from heterochromatin into neighboring euchromatin in set2Delta cells. Furthermore, genetic experiments demonstrated that cells lacking the Rpd3S-specific subunits Eaf3 or Rco1 did not display the anti-silencing phenotype of mutations in SET2 or H3-K36. Thus, antagonism of silencing is independent of the only known effector of this conserved histone modification.
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PMID:Histone H3 lysine 36 methylation antagonizes silencing in Saccharomyces cerevisiae independently of the Rpd3S histone deacetylase complex. 1717 83

Epigenetic systems are organized by different types of modifications on histones and DNA. To determine how epigenetic systems can produce variable, yet stable cellular outcomes, understanding the collaboration between these modifications is the key. A recent study by Yamagata and Kobayashi revealed the direct interplay between the regulation of two epigenetic modifications: DNA de-methylation by TET2 and histone H3-K36 methylation. Mechanistically, this finding could explain how cells are protected from oncogenesis by maintaining the integrity of active transcription. The recent identification of epigenetic modifier mutations in leukaemia suggested that it is not just the turning 'on' and 'off' of particular transcriptional events that causes disease occurrence, but rather it is the aberration in epigenetic regulation, i.e. the timing and duration of the activation/inactivation of these transcripts. Thus, a comprehensive understanding of how epigenetic interplays tune transcription will be the new perspective for disease research.
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PMID:Epigenetic interplays between DNA demethylation and histone methylation for protecting oncogenesis. 3060 33


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