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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2647-2652
PLENARY PAPER
The Stat5-RAR fusion protein represses transcription and
differentiation through interaction with a corepressor complex
Alexander B. Maurer,
Christian Wichmann,
Alexandra Gross,
Hana Kunkel,
Thorsten Heinzel,
Martin Ruthardt,
Bernd Groner, and
Manuel Grez
From the Georg-Speyer-Haus, Institute for Biomedical
Research, Frankfurt am Main, Germany, and University of Frankfurt,
Medical Clinic III, Frankfurt am Main, Germany.
The transcription factor Stat5 mediates the cellular response to
activation of multiple cytokine receptors involved in the regulation of
proliferation and differentiation of hematopoietic cells. Recently, the
human Stat5 gene was found to be translocated to the
RAR gene in a patient with acute promyelocytic leukemia indicating that Stat5 might also play a role in cellular
transformation. We investigated the mechanism by which Stat5 might
exert this function and studied the biochemical and cellular functions
of fusion proteins comprising Stat5 and RAR. The expression of
Stat5-RAR causes the transcriptional repression of gene
transcription, a process that requires the coiled-coil domain of Stat5
(amino acid positions 133-333). Oligomerization of this domain in the
Stat5-RAR fusion protein leads to stable binding of the corepressor
SMRT independent of all-trans retinoic acid (ATRA)
stimulation and is accompanied by an impaired response to
differentiation signals in hematopoietic cells. This inhibitory effect
on myeloid differentiation cannot be overcome by simultaneous
coexpression of RAR. We conclude that Stat5 is capable of
interacting with a corepressor complex that alters the pattern of
corepressor binding to RAR and its dissociation in response to ATRA
stimulation, leading to enhanced repressor activity and a block of
hematopoietic differentiation.
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