Dysregulation of apoptosis and a novel mechanism of defective apoptotic signal transduction in human B-cell neoplasms.
Apoptotic cell death is essential for normal B-cell development and for shaping the B-cell repertoire. Dysregulation of the Bcl-2 related proteins and alterations of the p53/p14ARF pathway are implicated in the pathogenesis and treatment resistance in human B-cell malignancies. We found a novel mechanism of dysregulated apoptosis in human B lymphoma Raji cells that differs from that of altered Bcl-2 and p53 functions. This cell line was resistant to nuclear apoptosis induced by various stimuli, and neither mitochondrial activation nor activation of caspase-3 led to DNA fragmentation. DNA in purified Raji nuclei was degraded in the presence of lysates from the apoptosis-sensitive cell line HL-60, whereas Raji cell lysates did not induce DNA fragmentation in HL-60 nuclei. Cleavage of ICAD/DFF-45 was normal. These results indicate that the apoptosis signal transduction pathway is defective downstream of caspase-3 in Raji cell cytoplasm. Therefore, exploring the molecular mechanism in this system should provide insight into apoptosis resistance in human B-cell malignancies.
Hirokawa
Makoto
M
Department of Internal Medicine III, Akita University School of Medicine, Japan. hirokawa@med.akita-u.ac.jp
Kawabata
Yoshinari
Y
Miura
Akira B
AB
D017209:Apoptosis / Q000502:physiology*; D006801:Humans; D015448:Leukemia, B-Cell / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000473:pathology*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*