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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-08-2474.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3668-3673
NEOPLASIA
Opposing effects of PML and PML/RAR on STAT3 activity
Akira Kawasaki,
Itaru Matsumura,
Yoshihisa Kataoka,
Eri Takigawa,
Koichi Nakajima, and
Yuzuru Kanakura
From the Department of Hematology and Oncology, Osaka
University Graduate School of Medicine; and the Department of
Immunology, Osaka City University Medical School, Osaka,
Japan.
Promyelocytic leukemia protein PML acts as a tumor suppressor,
whereas its chimeric mutant promyelocytic leukemia/retinoic acid
receptor (PML/RAR) causes acute promyelocytic leukemia (APL).
Because PML has been shown to form transcription-regulatory complexes
with various molecules, we speculated that PML and/or PML/RAR might
affect signal transducer and activator of transcription 3 (STAT3)
activity, which plays a crucial role in granulocyte colony-stimulating
factor (G-CSF)-induced growth and survival of myeloid cells.
In luciferase assays, PML inhibited STAT3 activity in NIH3T3, 293T,
HepG2, and 32D cells. PML formed a complex with STAT3 through B-box and
COOH terminal regions in vitro and in vivo, thereby inhibiting its DNA
binding activity. Although PML/RAR did not interact with STAT3, it
dissociated PML from STAT3 and restored its activity suppressed by PML.
To assess the biologic significance of these findings, we
introduced PML and PML/RAR into interleukin-3 (IL-3)-dependent
Ba/F3 cells expressing the chimeric receptor composed of extracellular
domain of G-CSF-R and cytoplasmic domain of gp130, in which
gp130-mediated growth is essentially dependent on STAT3 activity.
Neither PML nor PML/RAR affected IL-3-dependent growth of these
clones. By contrast, gp130-mediated growth was abrogated by PML,
whereas it was enhanced by PML/RAR. These results reveal new
functions of PML and PML/RAR and suggest that dysregulated STAT3
activity by PML/RAR may participate in the pathogenesis of APL.
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