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J. Biol. Chem., Vol. 275, Issue 43, 33567-33573, October 27, 2000
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From the Department of Physiology, The University of Texas Health
Science Center at San Antonio, San Antonio, Texas 78229-3900
dHAND and eHAND are basic helix-loop-helix
(bHLH) transcription factors expressed during embryogenesis and
are required for the proper development of cardiac and extraembryonic
tissues. HAND genes, like the myogenic bHLH genes, are classified as
class B bHLH genes, which are expressed in a tissue-restricted pattern and function by forming heterodimers with class A bHLH proteins. Myogenic bHLH genes are shown not to form homodimers efficiently, suggesting that their activity is dependent on their E-protein partners. To identify HIPs (HAND-interacting
proteins) that regulate the activity of the HAND genes, we
screened an 9.5-10.5-day-old mouse embryonic yeast two-hybrid library
with eHAND. Several HIPs held high sequence identity to eHAND,
indicating that eHAND could form and function as a homodimer. Based on
the high degree of amino acid identity between eHAND and dHAND, it is
possible that dHAND could also form homodimers and heterodimers with
eHAND. We show using yeast and mammalian two-hybrid assays as well as biochemical pull-down assays that eHAND and dHAND are capable of
forming both HAND homo- and heterodimers in vivo. To
investigate whether HAND genes form heterodimers with other
biologically relevant bHLH proteins, we tested and show HAND
heterodimerization with the recently identified Hairy-related
transcription factors, HRT1-3. This finding is exciting, because both
HRT and HAND genes are coexpressed in the developing heart and limb and
both have been implicated in establishing tissue boundaries and pattern
formation. Moreover, competition gel shift analysis demonstrates that
dHAND and eHAND can negatively regulate the DNA binding of MyoD/E12 heterodimers in a manner similar to MISTI and Id proteins, suggesting a
possible transcriptional inhibitory role for HAND genes. Taken together, these results show that dHAND and eHAND can form homo- and
heterodimer combinations with multiple bHLH partners and that this
broad dimerization profile reflects the mechanisms by which HAND genes
regulate transcription.
The Basic Helix-Loop-Helix Transcription factors
dHAND and eHAND Exhibit Dimerization
Characteristics That Suggest Complex Regulation of Function*
*
This work was supported by grants from the American Heart
Association and by National Institutes of Health Grant R01
HLA61677-01A1.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Physiology,
7756, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-4401; Fax:
210-567-4410; E-mail: firullia@UTHSCSA.edu.
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