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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2577-2585
Induction of apoptosis by extracellular ubiquitin in human
hematopoietic cells: possible involvement of STAT3 degradation by
proteasome pathway in interleukin 6-dependent hematopoietic cells
Hanako Daino,
Itaru Matsumura,
Koji Takada,
Junko Odajima,
Hirokazu Tanaka,
Shuji Ueda,
Hirohiko Shibayama,
Hirokazu Ikeda,
Masahiko Hibi,
Takashi Machii,
Toshio Hirano, and
Yuzuru Kanakura
From the Departments of Hematology/Oncology and Molecular Oncology,
Biomedical Research Center, Osaka University Medical School, Osaka, and
the Department of Biochemistry (I), Jikei University School of
Medicine, Tokyo, Japan.
The ubiquitin-proteasome pathway is responsible for selective
degradation of short-lived cellular proteins and is critical for the
regulation of many cellular processes. We previously showed that
ubiquitin (Ub) secreted from hairy cell leukemia cells had inhibitory
effects on clonogenic growth of normal hematopoietic progenitor cells.
In this study, we examined the effects of exogenous Ub on the growth
and survival of a series of human hematopoietic cells, including
myeloid cell lines (HL-60 and U937), a B-cell line (Daudi), and T-cell
lines (KT-3, MT-4, YTC-3, and MOLT-4). Exogenous Ub inhibited the
growth of various hematopoietic cell lines tested, especially of KT-3
and HL-60 cells. The growth-suppressive effects of Ub on KT-3 and HL-60
cells were almost completely abrogated by the proteasome inhibitor PSI
or MG132, suggesting the involvement of the proteasome pathway in this
process. Furthermore, exogenous Ub evoked severe apoptosis of KT-3 and
HL-60 cells through the activation of caspase-3. In interleukin-6
(IL-6)-dependent KT-3 cells, STAT3 was found to be conjugated by
exogenous biotinylated Ub and to be degraded in a proteasome-dependent
manner, whereas expression levels of STAT1, STAT5, or mitogen-activated
protein kinase were not affected. Moreover, IL-6-induced the
up-regulation of Bcl-2 and c-myc, and JunB was impaired in
Ub-treated KT-3 cells, suggesting that the anti-apoptotic and mitogenic
effects of IL-6 were disrupted by Ub. These results suggest that
extracellular Ub was incorporated into hematopoietic cells and mediated
their growth suppression and apoptosis through proteasome-dependent degradation of selective cellular proteins such as STAT3.
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