Beta(2)-microglobulin identified as an apoptosis-inducing factor and its characterization.
Major histocompatibility complex (MHC) molecules play an important role in antigen presentation for induction of tumor as well as cellular and humoral immunities. Recent studies using anti-MHC antibodies demonstrated that antibodies specific for HLA class I molecules induced cellular activation and a type of apoptosis that may be distinct from Fas-dependent or TNFR (tumor necrosis factor-alpha receptor)-dependent processes. We purified a previously untested apoptosis-inducing factor from HL-60 human leukemic cell-conditioned media to homogeneity and sequenced it. It was identified as beta(2)-microglobulin (beta(2)m), which has been previously known as thymotaxin and is a part of the HLA class I antigen complex. beta(2)m acts on both T-leukemic cells and myeloid leukemic cells to induce apoptosis, which then activates caspase 1 and 3. Cross-linking studies showed that biotinilated beta(2)m recognized an epitope distinct from those recognized by the anti-HLA class I antibody, as reported previously. We demonstrated that beta(2)m plays a previously unrecognized and important role in regulating the elimination of tumor cells, which occurs as a result of the action of beta(2)m as an apoptosis-inducing factor.
Mori
M
M
Department of Hematology and the Division of Molecular Hematopoiesis, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
Terui
Y
Y
Ikeda
M
M
Tomizuka
H
H
Uwai
M
M
Kasahara
T
T
Kubota
N
N
Itoh
T
T
Mishima
Y
Y
Douzono-Tanaka
M
M
Yamada
M
M
Shimamura
S
S
Kikuchi
J
J
Furukawa
Y
Y
Ishizaka
Y
Y
Ikeda
K
K
Mano
H
H
Ozawa
K
K
Hatake
K
K
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D017077:Culture Media, Conditioned / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D018922:HL-60 Cells / Q000737:chemistry; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D020298:U937 Cells / Q000187:drug effects; D001613:beta 2-Microglobulin / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology* / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D001613:beta 2-Microglobulin; D019014:fas Receptor; C096429:L 709049