1: Dev Biol. 2005 Jan 15;277(2):457-71. 

Range of HOX/TALE superclass associations and protein domain requirements for
HOXA13:MEIS interaction.

Williams TM, Williams ME, Innis JW.

Department of Human Genetics, University of Michigan, Med. Sci. II 4811, Ann
Arbor, MI 48109-0618, USA.

AbdB-like HOX proteins form DNA-binding complexes with the TALE superclass
proteins MEIS1A and MEIS1B, and trimeric complexes have been identified in
nuclear extracts that include a second TALE protein, PBX. Thus, soluble
DNA-independent protein-protein complexes exist in mammals. The extent of
HOX/TALE superclass interactions, protein structural requirements, and sites of
in vivo cooperative interaction have not been fully explored. We show that
Hoxa13 and Hoxd13 expression does not overlap with that of Meis1-3 in the
developing limb; however, coexpression occurs in the developing male and female
reproductive tracts (FRTs). We demonstrate that both HOXA13 and HOXD13 associate
with MEIS1B in mammalian and yeast cells, and that HOXA13 can interact with all
MEIS proteins but not more diverged TALE superclass members. In addition, the
C-terminal domains (CTDs) of MEIS1A (18 amino acids) and MEIS1B (93 amino acids)
are necessary for HOXA13 interaction; for MEIS1B, this domain was also
sufficient. We also show by yeast two-hybrid assay that MEIS proteins can
interact with anterior HOX proteins, but for some, additional N-terminal MEIS
sequences are required for interaction. Using deletion mutants of HOXA13 and
HOXD13, we provide evidence for multiple HOX peptide domains interacting with
MEIS proteins. These data suggest that HOX:MEIS interactions may extend to
non-AbdB-like HOX proteins in solution and that differences may exist in the
MEIS peptide domains utilized by different HOX groups. Finally, the capability
of multiple HOX domains to interact with MEIS C-terminal sequences implies
greater complexity of the HOX:MEIS protein-protein interactions and a larger
role for variation of HOX amino-terminal sequences in specificity of function.

PMID: 15617687 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


2: J Biol Chem. 2004 Jul 16;279(29):30287-97. Epub 2004 May 11. 

TALE homeodomain proteins regulate gonadotropin-releasing hormone gene
expression independently and via interactions with Oct-1.

Rave-Harel N, Givens ML, Nelson SB, Duong HA, Coss D, Clark ME, Hall SB, Kamps
MP, Mellon PL.

Department of Reproductive Medicine, School of Medicine, University of
California, San Diego, La Jolla, California 92903, USA.

Gonadotropin-releasing hormone (GnRH) is the central regulator of reproductive
function. Expression of the GnRH gene is confined to a rare population of
neurons scattered throughout the hypothalamus. Restricted expression of the rat
GnRH gene is driven by a multicomponent enhancer and an evolutionarily conserved
promoter. Oct-1, a ubiquitous POU homeodomain transcription factor, was
identified as an essential factor regulating GnRH transcription in the GT1-7
hypothalamic neuronal cell line. In this study, we conducted a two-hybrid
interaction screen in yeast using a GT1-7 cDNA library to search for specific
Oct-1 cofactors. Using this approach, we isolated Pbx1b, a TALE homeodomain
transcription factor that specifically associates with Oct-1. We show that
heterodimers containing Pbx/Prep1 or Pbx/Meis1 TALE homeodomain proteins bind to
four functional elements within the GnRH regulatory region, each in close
proximity to an Oct-1-binding site. Cotransfection experiments indicate that
TALE proteins are essential for GnRH promoter activity in the GT1-7 cells.
Moreover, Pbx1 and Oct-1, as well as Prep1 and Oct-1, form functional complexes
that enhance GnRH gene expression. Finally, Pbx1 is expressed in GnRH neurons in
embryonic as well as mature mice, suggesting that the associations between TALE
homeodomain proteins and Oct-1 regulate neuron-specific expression of the GnRH
gene in vivo.

PMID: 15138251 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


3: Oncogene. 2000 Feb 3;19(5):608-16. 

HoxA9-mediated immortalization of myeloid progenitors requires functional
interactions with TALE cofactors Pbx and Meis.

Schnabel CA, Jacobs Y, Cleary ML.

Department of Pathology, Stanford University School of Medicine, California
94305, USA.

Specific Hox genes are implicated in leukemic transformation, and their
selective genetic collaboration with TALE homeobox genes, Pbx and Meis,
accentuates their oncogenic potential. The molecular mechanisms underlying these
coordinate functions, however, have not been characterized. In this study, we
demonstrate that HoxA9 requires its Pbx interaction motif as well as its amino
terminus to enhance the clonogenic potential of myeloid progenitors in vitro. We
further show that HoxA9 forms functional trimeric DNA binding complexes with Pbx
and Meis-like proteins on a modified enhancer. DNA binding complexes containing
HoxA9 and TALE homeoproteins display cooperative transcriptional activity and
are present in leukemic cells. Trimeric complex formation on its own, however,
is not sufficient for HoxA9-mediated immortalization. Rather, structure-function
analyses demonstrate that domains of HoxA9 which are necessary for cellular
transformation are coincident with those required for trimer-mediated
transcriptional activation. Furthermore, the amino terminus of HoxA9 provides
essential transcriptional effector properties and its requirement for myeloid
transformation can be functionally replaced by the VP16 activation domain. These
data suggest that biochemical interactions between HoxA9 and TALE homeoproteins
mediate cellular transformation in hematopoietic cells, and that their
transcriptional activity in higher order DNA binding complexes provides a
molecular basis for their collaborative roles in leukemogenesis.

PMID: 10698505 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


4: EMBO J. 1998 Mar 2;17(5):1423-33. 

Prep1, a novel functional partner of Pbx proteins.

Berthelsen J, Zappavigna V, Mavilio F, Blasi F.

Dipartimento di Genetica e Biologia dei Microrganismi dell'Universita, DIBIT,
H.S. Raffaele, via Olgettina 58, 20132, Milan, Italy.

The human transcription factor, UEF3, is important in regulating the activity of
the urokinase plasminogen activator (uPA) gene enhancer. The UEF3 DNA target
site is a regulatory element in the promoters of several growth factor and
protease genes. We reported previously that purified UEF3 is a complex of
several subunits. In this paper we report the cloning of the cDNA of one of the
subunits which encodes for a novel human homeodomain protein, which we have
termed Prep1. The Prep1 homeodomain belongs to the TALE class of homeodomains,
is most closely related to those of the TGIF and Meis1 proteins, and like these,
recognizes a TGACAG motif. We further identify the other UEF3 subunit as a
member of the Pbx protein family. Unlike other proteins known to interact with
Pbx, Prep1 forms a stable complex with Pbx independent of DNA binding.
Heterodimerization of Prep1 and Pbx results in a strong DNA binding affinity
towards the TGACAG target site of the uPA promoter. Overall, these data indicate
that Prep1 is a stable intracellular partner of Pbx in vivo.

PMID: 9482739 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


5: Dev Dyn. 1997 Oct;210(2):173-83. 

Meis2, a novel mouse Pbx-related homeobox gene induced by retinoic acid during
differentiation of P19 embryonal carcinoma cells.

Oulad-Abdelghani M, Chazaud C, Bouillet P, Sapin V, Chambon P, Dolle P.

Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP,
College de France, Illkirch, C.U. de Strasbourg.

We report the cDNA cloning, partial genomic organization, and expression pattern
of Stra10, a novel retinoic acid-inducible gene in P19 embryonal carcinoma
cells. Four murine cDNA isoforms have been isolated, which are likely to result
from alternative splicing. The predicted protein sequences exhibit approximately
85% identity with the Pbx-related Meis1 homeobox gene products, which are
involved in myeloid leukemia in BXH-2 mice, and one of the Stra10 isoforms
corresponds to the recently published Meis2 sequence (Nakamura et al. [1996]
Oncogene 13:2235-2242). The Meis2 homeodomain is identical to that of Meis1, and
is most closely related to those of the Pbx/TGIF homeobox gene products. By in
situ hybridization analysis, we show that the Meis2 gene displays spatially
restricted expression patterns in the developing nervous system, limbs, face,
and in various viscera. In adult mice, Meis2 is mainly expressed in the brain
and female genital tract, with a different distribution of the alternative
splice forms in these organs.

PMID: 9337137 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


6: Genome Res. 1997 Feb;7(2):142-56. 

Identification of a conserved family of Meis1-related homeobox genes.

Steelman S, Moskow JJ, Muzynski K, North C, Druck T, Montgomery JC, Huebner K,
Daar IO, Buchberg AM.

Meis1 locus was isolated as a common site of viral integration involved in
myeloid leukemia in BXH-2 mice. Meis1 encodes a novel homeobox protein belonging
to the TALE (three amino acid loop extension) family of homeodomain-containing
proteins. The homeodomain of Meis1 is the only known motif within the entire
390-amino-acid protein. Southern blot analyses using the Meis1 homeodomain as a
probe revealed the existence family of Meis1-related genes (Mrgs) in several
diverged species. In addition, the 3' untranslated region (UTR) Meis1 was
remarkably conserved in evolution. To gain a further understanding of the role
Meis1 plays in leukemia and development, as well as to identify conserved
regions of the protein that might reveal function, we cloned and characterized
Mrgs from the mouse and human genomes. We report the sequence of Mrg1 and MRG2
as well as their chromosomal locations in murine and human genomes. Both Mrgs
share a high degree of sequence identity with the protein coding region of
Meis1. We have also cloned the Xenopus laevis ortholog of (XMeis1). Sequence
comparison of the murine and Xenopus clones reveals that Meis1 is highly
conserved throughout its coding sequence as well as the 3' UTR. Finally,
comparison of Meis1 and the closely related Mrgs to known homeoproteins suggests
that Meis1 represents a new subfamily of TALE homeobox genes.

Publication Types:
    Letter

PMID: 9049632 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------