Homeodomain revisited: a lesson from disease-causing mutations

In, Young

doi:10.1007/s00439-004-1252-1

Cited by 68 publications

(61 citation statements)

References 66 publications

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“…The I/V47, Q/K50, and N51 residues that recognize the core TAAT in the homeodomain-binding motif are not present in NSY-7. However, the hydrophobic residues that stabilize the homeodomain protein core are conserved or retain hydrophobic character in NSY-7, and several residues that interact with the DNA backbone are present (Draganescu and Tullius 1998;Fraenkel et al 1998;Chi 2005). The NSY-7 sequence is therefore consistent with a homeodomain-like structure that recognizes a noncanonical DNA sequence.…”

Section: Discussionmentioning

confidence: 95%

“…Engrailed residues that bind specific bases (open circles) or the DNA backbone (black circles) and residues that form the hydrophobic core (gray circles) are marked. Asterisks above the sequences mark residues important for homeodomain function (Gehring et al 1994;Draganescu and Tullius 1998;Fraenkel et al 1998;Sato et al 2004;Chi 2005). (C) Expression of srsx-3::GFP and str-2::dsRed in AWC neurons of wild type, nsy-7 mutants, C18F3.4-RNAi animals, and nsy-7(tm3080) rescued with a genomic clone or an odr-3::nsy-7 cDNA clone.…”

Section: Olfactory Cgmp Transduction Pathways Affect Both Awc On and mentioning

confidence: 99%

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Transcriptional regulation and stabilization of left–right neuronal identity in C. elegans

Lesch

Gehrke²,

Bulyk³

et al. 2009

Genes Dev.

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At discrete points in development, transient signals are transformed into long-lasting cell fates. For example, the asymmetric identities of two Caenorhabditis elegans olfactory neurons called AWC ON and AWC OFF are specified by an embryonic signaling pathway, but maintained throughout the life of an animal. Here we show that the DNAbinding protein NSY-7 acts to convert a transient, partially differentiated state into a stable AWC ON identity. Expression of an AWC ON marker is initiated in nsy-7 loss-of-function mutants, but subsequently lost, so that most adult animals have two AWC OFF neurons and no AWC ON neurons. nsy-7 encodes a protein with distant similarity to a homeodomain. It is expressed in AWC ON , and is an early transcriptional target of the embryonic signaling pathway that specifies AWC ON and AWC OFF ; its expression anticipates future AWC asymmetry. The NSY-7 protein binds a specific optimal DNA sequence that was identified through a complete biochemical survey of 8-mer DNA sequences. This sequence is present in the promoter of an AWC OFF marker and essential for its asymmetric expression. An 11-base-pair (bp) sequence required for AWC OFF expression has two activities: One region activates expression in both AWCs, and the overlapping NSY-7-binding site inhibits expression in AWC ON . Our results suggest that NSY-7 responds to transient embryonic signaling by repressing AWC OFF genes in AWC ON , thus acting as a transcriptional selector for a randomly specified neuronal identity.[Keywords: Homeodomain; olfactory development; transcriptional maintenance; transcriptional repression; activitydependent gene expression; cGMP-dependent protein kinase] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 95%

Section: Olfactory Cgmp Transduction Pathways Affect Both Awc On and mentioning

confidence: 99%

Transcriptional regulation and stabilization of left–right neuronal identity in C. elegans

Lesch

Gehrke²,

Bulyk³

et al. 2009

Genes Dev.

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“…2A, left). Mutations R189A, R237A, R237H, and R237P have been reported to eliminate the binding activity of HD to DNA, whereas Q234K alters its DNA-binding specificity (21). These HD mutations (R189A, Q234K, R237A, R237H, and R237P) lost the transcriptional activation for CDX2-target gene promoters ( Fig.…”

Section: Cdx2 Blocks Cell Proliferation Of Normal Adenoma and Carcinmentioning

confidence: 94%

Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1

et al. 2011

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Caudal-related homeoprotein CDX2 is expressed in intestinal epithelial cells, in which it is essential for their development and differentiation. A tumor suppressor function is suggested by evidence that CDX2 levels are decreased in human colon cancer specimens and that an inactivating mutation of Cdx2 in Apc D716 mice markedly increases the incidence of colonic polyps. In this study, we investigated roles for transcriptional and nontranscriptional functions of CDX2 in suppression of colonic tumorigenesis. Mutagenic analysis of CDX2 revealed that loss of function stabilizes CDK inhibitor p27 Kip1 by a nontranscriptional but homeodomaindependent mechanism that inhibits cyclin E-CDK2 activity and blocks G0/G1-S progression in colon cancer cells.

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“…Thus, even though the molecular bases of the functional disruptions have been elucidated, other mechanistic details that might be exploited for intervention await additional studies. Structural and functional data suggest that the key residues, including the mutational hot-spot arginine residues in POU H (22), might be targeted for small molecule or peptide development (58,59) in order to correct the defects in afflicted individuals or enhance the pancreatic β-cell function. (A) Comparison of HNF1β-DNA (purple) and HNF1αDNA (gold) (60) complexes.…”

Section: Disease-related Mutationsmentioning

confidence: 99%

Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β^,

2007

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HNF1β is an atypical POU transcription factor that participates in a hierarchical network of transcription factors controlling the development and proper function of vital organs such as liver, pancreas, and kidney. Many inheritable mutations on HNF1β are the monogenic causes of diabetes and several kidney diseases. To elucidate the molecular mechanism of its function and the structural basis of mutations, we have determined the crystal structure of human HNF1β DNA binding domain in complex with a high-affinity promoter. Disease-causing mutations have been mapped to our structure, and their predicted effects have been tested by a set of biochemical/ functional studies. These findings together with earlier findings with a homologous protein HNF1α, help us to understand the structural basis of promoter recognition by these atypical POU transcription factors and the site-specific functional disruption by disease-causing mutations.HNF1β (hepatocyte nuclear factor 1β; also known as vHNF1 or TCF2) is a widely distributed transcription factor that plays a critical role in early vertebrate development and embryonic survival (1-3). First identified as a key regulator in the liver, HNF1β is also expressed in the pancreas, kidney, lung, ovary, testis, and throughout the gastrointestinal tract. In pancreatic β-cells, HNF1β is known to form an integrated regulatory network with other transcription factors such as HNF1α, HNF4α, Pdx-1, Foxa2, and NeuroD1 for organ development and proper function (1,4). Thus, in humans, heterozygous mutations in the HNF1β gene have been linked to neonatal diabetes (5) and the autosomal dominant subtype of diabetes known as MODY (maturity-onset diabetes of the young) (6). Extrapancreatic diseases are also increasingly recognized in different organs, especially in the kidney, with a variety of renal developmental disorders such as renal cysts, familial hypoplastic glomerulocystic kidney disease, renal malformation, and atypical familial hyperuricaemic nephropathy (7-11).POU transcription factors, which include Pit-1, Oct-1, and Unc-86 as founding members and are now expanded to more than 13 members in humans, are developmental regulators of various neuroendocrine organs, and their sequence-specific DNA binding is mediated by a bipartite motif that consists of a POU homeodomain (POU H ) and POU-specific domain (POU S ) (12,13). POU H is a 60 amino acid classic homeodomain made of three α-helices with the third as a DNA recognition helix, while POU S is an additional ∼75 amino acid all-α-helical motif that cooperates with POU H to enhance the binding affinity and specificity of DNA binding ( Figures 1 and 2) (12,14). HNF1α (MODY3 gene product, the most commonly mutated MODY protein) and HNF1β (MODY5 gene product) are atypical members of the POU transcription factors. Their POU S domains have at least one additional α-helix at the N-terminus, and the second † This work was funded by the Juvenile Diabetes Research Foundation (1-2004-506) (8,24). Recently, HNF1β has also been associated wi...

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Homeodomain revisited: a lesson from disease-causing mutations

Cited by 68 publications

References 66 publications

Transcriptional regulation and stabilization of left–right neuronal identity in C. elegans

Transcriptional regulation and stabilization of left–right neuronal identity in C. elegans

Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1

Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β^,

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Homeodomain revisited: a lesson from disease-causing mutations

Cited by 68 publications

References 66 publications

Transcriptional regulation and stabilization of left–right neuronal identity in C. elegans

Transcriptional regulation and stabilization of left–right neuronal identity in C. elegans

Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1

Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β,

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Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β^,