Publications
78 results found
Mok CL, Gil-Gomez G, Williams O, et al., 1999, Bad can act as a key regulator of T cell apoptosis and T cell development, Journal of Experimental Medicine, Vol: 189, Pages: 575-586, ISSN: 0022-1007
Bad is a distant relative of Bcl-2 and acts to promote cell death. Here, we show that Bad expression levels are greatly increased in thymocytes during apoptosis. We generated bad transgenic mice to study the action of upregulated Bad expression on T cell apoptosis. The T cells from these mice are highly sensitive to apoptotic stimuli, including anti-CD95. The numbers of T cells are greatly depleted and the processes of T cell development and selection are perturbed. We show that the proapoptotic function of Bad in primary T cells is regulated by Akt kinase and that Bad overexpression enhances both cell cycle progression and interleukin 2 production after T cell activation. These data suggest that Bad can act as a key regulator of T cell apoptosis and that this is a consequence of its upregulation after exposure to death stimuli.
Brady HJ, Gil-Gómez G, 1999, The cell cycle and apoptosis., Results Probl Cell Differ, Vol: 23, Pages: 127-144, ISSN: 0080-1844
Gil-Gómez G, Berns A, Brady HJM, 1998, A link between cell cycle and cell death:: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis, EMBO JOURNAL, Vol: 17, Pages: 7209-7218, ISSN: 0261-4189
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- Citations: 166
Williams O, Norton T, Halligey M, et al., 1998, The action of bax and bcl-2 on T cell selection, Journal of Experimental Medicine, Vol: 188, Pages: 1125-1133, ISSN: 0022-1007
T cell development and selection in the thymus are shaped by the induction of apoptosis. However, a direct role in T cell development and selection for any of the molecules known to regulate apoptosis has remained controversial. We have studied the effect of bax and bcl-2 transgenes in recombination activation gene 1–deficient (RAG-1−/−) mice transgenic for the major histocompatibility complex class I–restricted F5 T cell receptor. Overexpression of a bax transgene in the thymus seriously impairs the production of mature T cells, whereas bcl-2 overexpression greatly promotes it. The effect of bax and bcl-2 overexpression on antigen-induced negative selection was studied using fetal thymic organ cultures. This analysis showed that Bcl-2 strongly inhibits negative selection, whereas Bax does not affect it. Our data directly show that Bcl-2 family members have specific roles in T cell selection and also lend support to the hypothesis that Bax and Bcl-2 can antagonize each other's action in a certain apoptosis pathway while in another they can be functionally nonreciprocal.
Gil-Gómez G, Brady HJM, 1998, Transgenic mice in apoptosis research, APOPTOSIS, Vol: 3, Pages: 215-228, ISSN: 1360-8185
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- Citations: 1
Brady HJ, Gil-Gómez G, 1998, Bax. The pro-apoptotic Bcl-2 family member, Bax., Int J Biochem Cell Biol, Vol: 30, Pages: 647-650, ISSN: 1357-2725
Bax is a pro-apoptotic member of the Bcl-2 family of genes which regulate programmed cell death. The Bax protein shares highly conserved domains with Bcl-2, some of which are required for the formation of Bax-Bcl-2 heterodimers. Bax expression is elevated in certain tissues after apoptotic stimuli and can be directly regulated by p53. Bax -/- mice have increased numbers of lymphoid cells and bax -/- neurons survive in culture following nerve growth factor deprivation. Bax can accelerate cell cycle entry in T-cells and has recently been shown to have a tumour suppressor function as well as carrying mutations in certain cancers. Bax can form ion-conducting channels in planar lipid bilayers which may be the biochemical mechanism through which it exerts its multiple effects. Pharmacological manipulation of Bax has implications for many diseases involving apoptosis such as cancer or neurodegenerative disorders.
Salomons GS, Brady HJM, VerwijsJanssen M, et al., 1997, The Bax alpha:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia, INTERNATIONAL JOURNAL OF CANCER, Vol: 71, Pages: 959-965, ISSN: 0020-7136
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- Citations: 126
Brady HJM, GilGomez G, Kirberg J, et al., 1996, Bax alpha perturbs T cell development and affects cell cycle entry of T cells, EMBO JOURNAL, Vol: 15, Pages: 6991-7001, ISSN: 0261-4189
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- Citations: 150
Brady HJM, Salomons GS, Bobeldijk RC, et al., 1996, T cells from bax alpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53, EMBO JOURNAL, Vol: 15, Pages: 1221-1230, ISSN: 0261-4189
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- Citations: 123
BRADY HJM, ABRAHAM DJ, PENNINGTON DJ, et al., 1995, ALTERED CYTOKINE EXPRESSION IN T-LYMPHOCYTES FROM HUMAN-IMMUNODEFICIENCY-VIRUS TAT TRANSGENIC MICE, JOURNAL OF VIROLOGY, Vol: 69, Pages: 7622-7629, ISSN: 0022-538X
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- Citations: 22
BRADY HJM, PENNINGTON DJ, DZIERZAK EA, 1994, TRANSGENIC MICE AS MODELS OF HUMAN-IMMUNODEFICIENCY-VIRUS EXPRESSION AND RELATED CELLULAR EFFECTS, JOURNAL OF GENERAL VIROLOGY, Vol: 75, Pages: 2549-2558, ISSN: 0022-1317
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- Citations: 10
BRADY HJM, MILES CG, PENNINGTON DJ, et al., 1994, SPECIFIC ABLATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TAT-EXPRESSING CELLS BY CONDITIONALLY TOXIC RETROVIRUSES, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 91, Pages: 365-369, ISSN: 0027-8424
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- Citations: 37
BRADY HJM, PENNINGTON DJ, MILES CG, et al., 1993, CD4 cell surface downregulation in HIV‐1 Nef transgenic mice is a consequence of intracellular sequestration., The EMBO Journal, Vol: 12, Pages: 4923-4932, ISSN: 0261-4189
The Nef gene product is a regulatory protein of HIV whose biological function is poorly understood. Nef has been thought to have a negative effect on viral replication in vitro but has been shown in studies with SIV to be necessary in the establishment of viraemia in vivo. In vitro studies in various human cell lines have shown that Nef downregulates the expression of cell surface CD4 and thus could have effects on the immune response. We have generated four transgenic mouse lines, with constructs containing two different Nef alleles under the control of CD2 regulatory elements to examine the interaction of Nef with the host immune system in vivo. In adult transgenic mice we have found marked downregulation in the level of CD4 on the surface of double positive thymocytes and a decrease in the number of CD4+ T cells in the thymus. Functional analyses have revealed a decrease in the total activation of transgenic thymocytes by anti‐CD3 epsilon antibody. By specific intracellular staining of T cells in such mice we have found CD4 colocalizing with a Golgi‐specific marker. These results strongly suggest a Nef mediated effect on developing CD4 thymocytes resulting from interference of Nef in the intracellular trafficking or post‐translational modification of CD4.
BRADY HJM, MILES CG, PENNINGTON DJ, et al., 1993, STUDIES OF HIV-2 PROMOTER ACTIVITY AND CELL-SPECIFIC ABLATION, LEUKEMIA, Vol: 7, Pages: S61-S65, ISSN: 0887-6924
BRADY HJM, LOWE N, SOWDEN JC, et al., 1991, THE HUMAN CARBONIC ANHYDRASE-I GENE HAS 2 PROMOTERS WITH DIFFERENT TISSUE SPECIFICITIES, BIOCHEMICAL JOURNAL, Vol: 277, Pages: 903-905, ISSN: 0264-6021
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- Citations: 13
LOWE N, BRADY HJM, BARLOW JH, et al., 1990, STRUCTURE AND METHYLATION PATTERNS OF THE GENE ENCODING HUMAN CARBONIC ANHYDRASE-I, GENE, Vol: 93, Pages: 277-283, ISSN: 0378-1119
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- Citations: 27
BRADY HJM, EDWARDS M, LINCH DC, et al., 1990, EXPRESSION OF THE HUMAN CARBONIC ANHYDRASE-I GENE IS ACTIVATED LATE IN FETAL ERYTHROID DEVELOPMENT AND REGULATED BY STAGE-SPECIFIC TRANS-ACTING FACTORS, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 76, Pages: 135-142, ISSN: 0007-1048
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- Citations: 20
BRADY HJM, SOWDEN JC, EDWARDS M, et al., 1989, MULTIPLE GF-1 BINDING-SITES FLANK THE ERYTHROID SPECIFIC TRANSCRIPTION UNIT OF THE HUMAN CARBONIC ANHYDRASE-I GENE, FEBS LETTERS, Vol: 257, Pages: 451-456, ISSN: 0014-5793
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- Citations: 29
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