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Blood, 1 January 2007, Vol. 109, No. 1, pp. 100-108.
Prepublished online as a Blood First Edition Paper on August 3, 2006; DOI 10.1182/blood-2006-02-003590.
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Submitted February 13, 2006
Accepted June 22, 2006
Diminished proteasomal degradation results in
accumulation of Gfi1 protein levels in monocytes
Jurgen A.F. Marteijn, Laurens T. van der Meer, Liesbeth van Emst, Theo de Witte, Joop H. Jansen, and Bert A. van der Reijden*
Central Hematology Laboratory, Radboud University Nijmegen, Nijmegen, The Netherlands
* Corresponding author; email: b.vanderreijden{at}chl.umcn.nl.
Gfi1 is a transcriptional repressor essential during
myeloid differentiation. Gfi1-/- mice exhibit a block in
myeloid differentiation resulting in the accumulation of
an immature myelo-monocytic cell population and the
complete absence of mature neutrophils. Even though mRNA
levels of Gfi1 appear to be very low in monocytes, Gfi1
might play a role in the monocytic lineage as Gfi1-/-
mice exhibit diminished monocyte-derived dendritic cells
and disturbed cytokine production by macrophages in
response to LPS. We show here that Gfi1 protein levels
are mainly regulated by the ubiquitin-proteasome system.
Upon forced monocytic differentiation of U937 cells Gfi1
mRNA levels dropped but protein levels increased due to
diminished proteasomal turnover. Similarly, Gfi1 mRNA
levels are low in primary monocytes while the protein is
clearly detectable. Conversely, Gfi1 mRNA levels are
high in granulocytes but the protein is swiftly degraded
by the proteasome in these cells. Chromatin
immunoprecipitation experiments showed that Gfi1 binds
to the promoter of several granulocytic specific genes
in primary monocytes, including C/EBP ,
neutrophil elastase and Gfi1 itself. The binding of the
repressor Gfi1 to these promoters correlated with low
expression of these genes in monocytes compared to
granulocytes. Our data fit a model in which Gfi1 protein
levels are induced in primary monocytes, due to
diminished proteasomal degradation, to repress genes
that play a role in granulocytic differentiation.
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