Cell-mediated cytotoxicity can be regulated by p53 tumor suppressor gene activity in vitro.
The wild-type human p53 tumor suppressor gene was tested for its ability to modulate cytotoxic activity of in vitro activated peripheral blood lymphocytes. Peripheral blood mononuclear cells (PBMCs) were stimulated by phytohemagglutinin (PHA), interferon alpha 2b (IFN alpha 2b), interleukin 2 (IL-2) or their combinations to induce cytotoxicity. This stimulation significantly increased the percentage of cells expressing p53, which was at its maximum when induced by IL-2 combined with IFN alpha 2b. The role of p53 in the modulation of different aspects of cytotoxic activity of these cells was analyzed by studying the effects of p53 abrogation by antisense oligonucleotide (p53 AS) treatment in comparison with p53 sense or scrambled (missense) oligonucleotide (p53 S or p53 MS) treatment. We show that p53 plays a key role through induction of apoptosis in target cells (tumor necrosis factor pathway) rather than through osmolytic degeneration (perforin pathway) which is only slightly increased by p53 abrogation. Meanwhile, in vitro abrogation of p53 expression in PBL was found to be accompanied by an increase of CD8+ lymphocytes and an important increase of the CD56 'bright' NK cell sub-population.
Mahdi
T
T
Laboratoire de Biologie Cellulaire et Moléculaire, CHU de Poitiers, France.
Tanzer
J
J
Brizard
A
A
Guilhot
F
F
Babin
P
P
Kitzis
A
A
D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis; D017209:Apoptosis; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000502:physiology*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D013873:Thionucleotides; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D015703:Antigens, CD; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013873:Thionucleotides; D016159:Tumor Suppressor Protein p53