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Myb and Ets Proteins Are Candidate Regulators of
c-kit Expression in Human Hematopoietic Cells
Mariusz Z. Ratajczak,
Danilo Perrotti,
Paola Melotti,
Mark Powzaniuk,
Bruno Calabretta,
Kuzufumi Onodera,
David A. Kregenow,
Bogdan Machalinski, and
Alan M. Gewirtz
From the Departments of Pathology and Internal Medicine, University
of Pennsylvania School of Medicine, Philadelphia, PA and the Department
of Microbiology and Immunology and Kimmel Cancer Center, Thomas
Jefferson University, Philadelphia, PA
Kit is a tyrosine kinase receptor that plays an
important role in human hematopoietic cell growth. The promoter
elements that modulate the gene's expression have not been extensively
studied. Because of c-kit's acknowledged importance in
hematopoiesis, we sought to address this issue in more detail. To
perform these studies we analyzed a human c-kit 5
flanking fragment ~1 kilobase in length. Deletion constructs showed a
region ~139 nucleotides upstream from the translation initiation site
that was critical for promoter activity. A region containing a
potential silencing element was also identified. Sequence analysis
indicated several potential Myb- and Ets-binding sites.
The functional significance of these sites was explored by showing that
both wild-type Myb and Ets-2 protein, but not a DNA
binding-deficient Myb mutant protein, bound to distinct
5 flanking fragments that included these sites. Furthermore,
binding of recombinant Myb and Ets-2 protein to these
fragments could be competed with an excess of double stranded
oligodeoxynucleotides containing canonical, but not mutated,
Myb- or Ets-binding sites. We also showed that the 5 flanking region of c-kit exhibited promoter activity
in nonhematopoietic cells only when the cells were transfected with
c-myb or ets-2 expression vectors. Moreover,
Myb and Ets-2 coexpression in such cells augmented
transactivation of c-kit promoter constructs in comparison to
that observed in cells transfected with either construct alone.
Promoter constructs lacking various Myb and Ets sites
deleted were much less effective in this same system. Finally,
Myb and Ets-2 mRNA expression was detected in
CD34+, Kit low as well as
CD34+, Kit bright cells. In aggregate,
these data further define the human c-kit promoter's
functional anatomy and suggest that Myb and Ets
proteins play an important, perhaps cooperative, role in regulating
expression of this critical hematopoietic cell receptor.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1934-1946
© 1998 by The American Society of Hematology.
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