Homeodomain Proteins

Gehring, Walter J.; Affolter, Markus; Bürglin, Thomas R.

doi:10.1146/annurev.bi.63.070194.002415

Cited by 880 publications

(716 citation statements)

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“…This could be due to differences in binding and transcription activity in an in vivo three-dimensional DNA structure and the in vitro binding between DNA and protein in an EMSA and/or to the requirement, for full binding activity, of protein domains outside the homeodomain. Regardless of the explanation for this discrepancy, the results are not without precedent, since domains with relatively weaker binding activities have been reported to be important in the in vivo action of homeodomain-containing proteins (50). Our results also show that in addition to the site at Ϫ125, binding domains at Ϫ446 and Ϫ14 are important but not critical for the transactivation of AoGen by TTF-1.…”

Section: Ttf-1 Regulates Ang Transcription In Subfornical Organcontrasting

confidence: 61%

TTF-1, a Homeodomain-containing Transcription Factor, Participates in the Control of Body Fluid Homeostasis by Regulating Angiotensinogen Gene Transcription in the Rat Subfornical Organ

Son

Hur

Ryu

et al. 2003

Journal of Biological Chemistry

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In recent years, it has become increasingly evident that angiotensins synthesized in the brain contribute to regulating body fluid homeostasis. Although angiotensinogen, the unique angiotensin precursor, is produced in the brain, the factors that regulate its gene expression remain unknown. We recently found that TTF-1, a homeodomain-containing transcription factor essential for the development of the fetal diencephalon, is postnatally expressed in discrete areas of the hypothalamus. We now report that the subfornical organ, an important site of angiotensinogen synthesis, is an extrahypothalamic site of TTF-1 expression. Double in situ hybridization histochemistry demonstrated the presence of TTF-1 mRNA in angiotensinogen-producing cells of the rat subfornical organ. RNase protection assays showed that TTF-1 and angiotensinogen mRNA levels are simultaneously increased in the subfornical organ by water deprivation. The angiotensinogen promoter contains seven presumptive TTF-1 binding motifs, four of which are recognized by the TTF-1 homeodomain. In the C6 glioma cell line, TTF-1 transactivates the angiotensinogen promoter in a dose-dependent manner. This transactivation is abolished by deletion of the TTF-1 binding motif at ؊125. Intracranial administration of an antisense TTF-1 oligodeoxynucleotide decreased angiotensinogen mRNA in the subfornical organ and dramatically reduced the animal's water intake while increasing urine excretion. Moreover, plasma arginine vasopressin content was decreased by the same treatment. These results demonstrate a novel role for TTF-1 in the regulation of body fluid homeostasis, exerted via the transactivational control of angiotensinogen synthesis in the subfornical organ.The control of body fluid volume and blood pressure is a critical homeostatic process required for normalcy of the internal environment and for the preservation of life. Many studies have demonstrated that the renin-angiotensin system (RAS) 1 plays an important role in the regulation of fluid volume balance, blood pressure, and other related biological responses through the generation of angiotensin II (ANG II) (1). The existence of a brain RAS in addition to the peripheral RAS has also been established (2, 3). All components of the peripheral RAS have been found in the brain, most notably in the subfornical organ (SFO). The SFO is a circumventricular organ (CVO) of the lamina terminalis located at the top of the dorsal third ventricle (4). It is composed of fenestrated capillary loops in addition to glial cells, but in contrast to other CVOs such as the median eminence of the hypothalamus, it also contains neuronal cell bodies (1, 5). The SFO of rats contains high concentrations of angiotensinogen (AoGen) (6), the angiotensin precursor; renin-like activity (that converts AoGen to ANG I) (7); angiotensin-converting enzyme (which converts ANG I to ANG II) (8); the peptide ANG II (9); and AT 1 -type ANG II receptors (3). Thus, the SFO is not only a target for circulating ANG II, which exerts a potent dipsogenic ef...

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Section: Ttf-1 Regulates Ang Transcription In Subfornical Organcontrasting

confidence: 61%

TTF-1, a Homeodomain-containing Transcription Factor, Participates in the Control of Body Fluid Homeostasis by Regulating Angiotensinogen Gene Transcription in the Rat Subfornical Organ

Son

Hur

Ryu

et al. 2003

Journal of Biological Chemistry

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“…The Pbx-NFPP complex was further distinct in its recognition of a variant motif in which the third A in the NFPP binding core, which is essential for Pbx-Hox binding to TGATTGAT and which binds the invariant Asn 51 in the Hox HD, could be altered to G without appreciable loss of complex formation. The fact that a hydrogen bond between Asp51 of Hox HDs and this adenine is essential for binding of Hox proteins to their DNA targets suggests that NFPP may not be a HD protein (Desplan et al, 1988;Kissinger et al, 1990;Laughon, 1991;Gehring et al, 1994). NFPP was also distinct from Class I Hox proteins in its failure to form heterodimers with endogenous E2a-Pbx1, even though E2a-Pbx1 was active as demonstrated by its ability to heterodimerize with exogenous HoxA5 on a PRS.…”

Section: Discussionmentioning

confidence: 99%

The highest affinity DNA element bound by Pbx complexes in t(1;19) leukemic cells fails to mediate cooperative DNA-binding or cooperative transactivation by E2a-Pbx1 and Class I Hox proteins – evidence for selective targetting of E2a-Pbx1 to a subset of Pbx-recognition elements

Knoepfler

Kamps

1997

Oncogene

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“…Among them, Hox genes belonging to the Abd-B subfamily of the HoxA and HoxD cluster are expressed in the limb mesenchyme in a position-specific fashion (3)(4)(5) and are known to provide the positional cue for limb cartilage pattern formation (6 -8). The Hox genes encode homeodomain proteins that function as transcriptional regulators of downstream target genes through DNA binding by the homeodomain (9). Genes controlling the cell cycle and cell adhesion have been reported to be Hox targets (10 -12); however, the target genes of Abd-B homeoproteins during limb cartilage formation have not yet been identified.…”

mentioning

confidence: 99%

Hox Proteins Functionally Cooperate with the GC Box-binding Protein System through Distinct Domains

Suzuki

Ueno

Kuroiwa

2003

Journal of Biological Chemistry

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Hox genes encode a transcriptional factor that plays a key role in regulating position-specific cartilage pattern formation. We found that Hoxa-13 and Hoxd-13, which are members of the Abd-B subfamily of Hox genes and are crucial for the autopod development of the limb, stimulate transcription from the Bmp-4 promoter. This stimulation was dependent on the GC box within the promoter and independent of the putative Hox protein binding site. The stimulation by HoxA-13 was remarkably enhanced by cotransfection with members of a family of zinc finger GC box binding transcriptional factors including Sp1. The stimulation was suppressed by another Abd-B Hox protein, HoxA-11, indicating that each Abd-B Hox protein has a different effect on the target genes through the Sp1 system. We have identified multiple functional domains involved in transcriptional regulation, including three independent transcriptional activation domains (ADs) in HoxA-13. AD1 and AD3 in helices 1 and 2 of the homeodomain individually cooperate with Sp1-dependent stimulation. The homeodomain is also required for cooperation of the AD with Sp1. By contrast, AD2 strongly activates transcription in an Sp1-independent manner only when the homeodomain has been removed. These observations indicate that HoxA-13 regulates transcription through multiple pathways. In addition, we found that a helix 3 mutation of the HoxA-13 homeodomain behaves as a dominant negative form.

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Homeodomain Proteins

Cited by 880 publications

References 0 publications

TTF-1, a Homeodomain-containing Transcription Factor, Participates in the Control of Body Fluid Homeostasis by Regulating Angiotensinogen Gene Transcription in the Rat Subfornical Organ

TTF-1, a Homeodomain-containing Transcription Factor, Participates in the Control of Body Fluid Homeostasis by Regulating Angiotensinogen Gene Transcription in the Rat Subfornical Organ

The highest affinity DNA element bound by Pbx complexes in t(1;19) leukemic cells fails to mediate cooperative DNA-binding or cooperative transactivation by E2a-Pbx1 and Class I Hox proteins – evidence for selective targetting of E2a-Pbx1 to a subset of Pbx-recognition elements

Hox Proteins Functionally Cooperate with the GC Box-binding Protein System through Distinct Domains

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