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J. Biol. Chem., Vol. 276, Issue 7, 4570-4580, February 16, 2001
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§,,
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From the Csx/Nkx2.5 is an evolutionarily conserved
homeodomain (HD)-containing transcription factor that is essential for
early cardiac development. We found that the HD of Csx/Nkx2.5 binds as
a monomer as well as a dimer to its DNA binding sites in the promoter
of the atrial natriuretic factor (ANF) gene, an in vivo
target gene of Csx/Nkx2.5. Csx/Nkx2.5 physically interacts with each
other in vitro as well as in cells, and the HD is critical
for homodimerization. Lys193 and Arg194,
located at the COOH-terminal end of HD, are essential for dimerization. Lys193 is also required for a specific interaction with the
zinc finger transcription factor GATA4. Csx/Nkx2.5 can heterodimerize
with other NK2 homeodomain proteins, Nkx2.3 and Nkx2.6/Tix, with
different affinities. A single missense mutation, Ile183 to
Pro in the HD of Csx/Nkx2.5, preserved homodimerization function, but
totally abolished DNA binding. Ile183 Cardiovascular Division and the
¶ Division of Endocrinology, Beth Israel Deaconess Medical
Center, Department of Medicine, Harvard Medical School, Boston,
Massachusetts 02215, the ** Section of Cancer Biology, Radiation
Oncology Center, Washington University School of Medicine, St. Louis,
Missouri 63108, and the Department of Molecular
Cardiovascular Biology, Yamaguchi University School of Medicine,
1-1-1 Minami-kogushi, Ube 755-8505, Japan
Pro mutant
acts in an inhibitory manner on wild type Csx/Nkx2.5 transcriptional
activity through the ANF promoter in 10T1/2 cells. However,
Ile183 Pro mutant does not inhibit wild type Csx/Nkx2.5
function on the ANF promoter in cultured neonatal cardiac myocytes,
possibly due to failure of dimerization in the presence of the target
DNA. These results suggest that complex protein-protein interactions of
Csx/Nkx2.5 play a role in its transcriptional regulatory function.
To whom correspondence may be addressed: Beth Israel Deaconess
Medical Center, 330 Brookline Ave. SL201, Boston, MA 02215. Tel.:
617-667-4858; Fax: 617-975-5268; E-mail: sizumo@caregroup.harvard.edu.
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