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PubMed1997

The yeast ATP binding cassette (ABC) protein genes PDR10 and PDR15 are novel targets for the Pdr1 and Pdr3 transcriptional regulators.

The yeast transcription factors Pdr1 and Pdr3 control pleiotropic drug resistance (PDR) development, since they regulate expression of ATP-binding cassette (ABC) drug efflux pumps through binding to cis-acting sites known as PDREs (PDR responsive elements). In this report, we show by Northern blotting, gel shift mobility assays and DNase I footprinting that transcription of the ABC genes PDR10 and PDR15 is also controlled by Pdr1 and Pdr3. In addition, in vitro band shift assays demonstrate that a GST-Pdr1 fusion protein can bind to the PDREs of PDR10 and PDR15. DNase I footprinting allowed the identification of the precise PDRE binding motifs, indicating the presence of a novel slightly degenerate PDRE motif in the PDR15 promoter. Finally, PDR10 and PDR15 mRNA levels vary dramatically in abundance in isogenic yeast strains carrying either deltapdr1, deltapdr3 and deltapdr1 deltapdr3 deletions or pdr1-3 and pdr3-2 gain-of-function mutations, demonstrating that both PDR10 and PDR15 are new members of the yeast PDR network.

ATP-Binding Cassette Transporters↗
PubMed1997

Craniofacial abnormalities induced by the ectopic expression of homeobox genes.

In this paper I have tried to bring together work that highlights the role of homeobox genes in generating craniofacial form. I review both normal and disrupted embryogenesis and ask whether mis-expression of the homeobox genes outside their normal domains could be contributing to congenital facial abnormalities arising from either genetic or teratogenic actions. Experimentally generated transgenic mice carrying loss- or gain-of-function mutations in homeobox genes, in combination with their normal expression patterns, have allowed us to compile and test models of embryonic specification based around a Hox/homeobox code. These models form the basis on which the functional questions are considered. There are four major sections covering different experimental approaches designed to ectopically induce homeobox genes in the head. Transgenic mice, where heterologous promoters drive a given Hox gene in the head, have shown that the more posteriorly expressed Hox genes tend to have a significant effect only on the skull bones of mesodermal origin whereas those normally expressed more anteriorly, in the hindbrain and branchial arches, can affect more anterior branchial arch and neural crest-derived structures. Manipulation experiments which can induce homeobox genes in small, localised regions of the facial precursors show clear and dramatic effects of this expression on facial development. Null mutations in predicted repressors of Hox gene expression, however, do not appear to give rise to substantial craniofacial abnormalities. Retinoic acid, on the other hand, is well known for its teratogenic actions and its ability to induce Hox gene expression. Evidence is now accumulating that at least some of its teratogenic actions may be mediated by its regulation of the Hox and other homeobox genes in the head.

Abnormalities, Drug-Induced↗
PubMed1995

The Janus protein tyrosine kinase family and its role in cytokine signaling.

During the past 2 years, research from quite divergent areas has converged to provide the first insights into the mechanisms by which cytokines that utilize receptors of the cytokine receptor superfamily function. On the one hand, the obscure Jak family of cytoplasmic protein tyrosine kinases was independently implicated in IFN and hematopoietic growth factor signaling. Recent studies have expanded these initial observations to demonstrate that Jaks are critical to the functioning of all the receptors of the cytokine receptor superfamily. A variety of questions remain to be explored regarding the structure and function of Jaks and their interaction with receptors. It will also be important to pursue additional approaches to determine if the Jaks are necessary for various biological responses, particularly for mitogenic responses. The second major area of convergence has been the demonstration that members of the Stat family of transcription factors, initially identified in IFN-regulated gene expression, are generally involved in cytokine signaling. Clearly, a number of Stat-like activities remain to be cloned and it can be anticipated that the family contains additional members. Although a variety of genes are known to be regulated by the Stats association with IFN responses, much less is known concerning the genes regulated by the new Stats in cytokine signaling. Of particular importance is information relating to their potential contribution to mitogenic responses. From a biochemical standpoint, the Stats represent a remarkable family of proteins with regard to the ability of the modification of a single tyrosine residue to so dramatically affect cellular localization and DNA binding activity. Studies to identify the domains involved, and associated proteins that might contribute to either property, will be of considerable interest. More generally, it can hypothesized that Jaks and Stats, if important for proliferation and differentiation, may be the targets for malignant transformation. Although none of the genes map to chromosomal breakpoints that have been implicated in transformation, gain of function mutations is a likely mechanism that needs to be explored. Similarly, the Jak-Stat pathway would appear to be an excellent target for the development of drugs that affect a variety of cytokine functions.

Base Sequence↗
PubMed1996

Fibroblast growth factor receptor 3 is a negative regulator of bone growth.

Endochondral ossification is a major mode of bone that occurs as chondrocytes undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. We have identified a role for fibroblast growth factor receptor 3 (FGFR-3) in this process by disrupting the murine Fgfr-3 gene to produce severe and progressive bone dysplasia with enhanced and prolonged endochondral bone growth. This growth is accompanied by expansion of proliferating and hypertrophic chondrocytes within the cartilaginous growth plate. Thus, FGFR-3 appears to regulate endochondral ossification by an essentially negative mechanism, limiting rather than promoting osteogenesis. In light of these mouse results, certain human disorders, such as achondroplasia, can be interpreted as gain-of-function mutations that activate the fundamentally negative growth control exerted by the FGFR-3 kinase.

Animals↗
PubMed1998

The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9.

Gain-of-function mutations in the Caenorhabditis elegans gene egl-1 cause the HSN neurons to undergo programmed cell death. By contrast, a loss-of-function egl-1 mutation prevents most if not all somatic programmed cell deaths. The egl-1 gene negatively regulates the ced-9 gene, which protects against cell death and is a member of the bcl-2 family. The EGL-1 protein contains a nine amino acid region similar to the Bcl-2 homology region 3 (BH3) domain but does not contain a BH1, BH2, or BH4 domain, suggesting that EGL-1 may be a member of a family of cell death activators that includes the mammalian proteins Bik, Bid, Harakiri, and Bad. The EGL-1 and CED-9 proteins interact physically. We propose that EGL-1 activates programmed cell death by binding to and directly inhibiting the activity of CED-9, perhaps by releasing the cell death activator CED-4 from a CED-9/CED-4-containing protein complex.

Amino Acid Sequence↗
PubMed2001

The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation.

Evolution of the human heart has incorporated a variety of successful strategies for motion used throughout the animal kingdom. One such strategy is to add the efficiency of torsion to compression so that blood is wrung, as well as pumped, out of the heart. Models of cardiac torsion have assumed uniform contractile properties of muscle fibers throughout the heart. Here, we show how a spatial gradient of myosin light chain phosphorylation across the heart facilitates torsion by inversely altering tension production and the stretch activation response. To demonstrate the importance of cardiac light chain phosphorylation, we cloned a myosin light chain kinase from a human heart and have identified a gain-in-function mutation in two individuals with cardiac hypertrophy.

Animals↗
PubMed2003

AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart.

Myocardial ischemia is the leading cause of all cardiovascular deaths in North America. Myocardial ischemia is accompanied by profound changes in metabolism including alterations in glucose and fatty acid metabolism, increased uncoupling of glucose oxidation from glycolysis and accumulation of protons within the myocardium. These changes can contribute to a poor functional recovery of the heart. One key player in the ischemia-induced alteration in fatty acid and glucose metabolism is 5'AMP-activated protein kinase (AMPK). Accumulating evidence suggest that activation of AMPK during myocardial ischemia both increases glucose uptake and glycolysis while also increasing fatty acid oxidation during reperfusion. Gain-of-function mutations of AMPK in cardiac muscle may also be causally related to the development of hypertrophic cardiomyopathies. Therefore, a better understanding of role of AMPK in cardiac metabolism is necessary to appropriately modulate its activity as a potential therapeutic target in treating ischemia reperfusion injuries. This review attempts to update some of the recent findings that delineate various pathways through which AMPK regulates glucose and fatty acid metabolism in the ischemic myocardium.

AMP-Activated Protein Kinases↗
PubMed2001

Inherited disorders of GnRH and gonadotropin receptors.

Gonadotropin and GnRH receptors belong to the family of G protein coupled receptors. Gain of function mutations have been described, yielding constitutively active receptors. In the case of the LH receptor these dominant mutations determine familial male limited precocious puberty. Somatic mutations of this receptor may in some cases provoke Leydig-cell adenomas. The constitutive LH receptor is not associated with female precocious puberty. Inactivating mutations are recessive. Alterations in the GnRH receptor determine hypogonadotropic hypogonadism. The clinical diagnosis of this etiology of hypogonadism is extremely difficult, especially in sporadic cases. Mutations of gonadotropin receptors determine primary amenorrhea in girls, whereas in boys they are responsible for Leydig cell aplasia or hypoplasia (LH receptor) or of a variable alteration of spermatogenesis (FSH receptor). Mutations provoking only partial alterations of receptor functions are relatively more frequent, than those inducing complete receptor inactivity. They provide interesting insights into the physiology of GnRH and gonadotropin action.

Female↗
PubMed2000

Expression of the c-kit protein is associated with certain subtypes of salivary gland carcinoma.

The c-Kit protein, a receptor type tyrosine kinase that plays an important role in the development of hematopoietic cells, melanocytes, and germ cells, is expressed in mastocytosis, gastrointestinal stromal cell tumors (GISTs), germ cell tumors, and several other tumors. Gain-of-function mutations in exon 11 and exon 17 have been shown as a mechanism of c-kit activation in some tumors. To study the role of c-kit in salivary gland carcinomas, we analyzed the c-kit protein expression in 79 carcinomas of major and minor salivary glands by immunohistochemistry. Although varying in intensity of staining, c-kit expression was identified very often in adenoid cystic carcinomas (20/25), lymphoepithelioma-like carcinomas (6/6) and myoepithelial carcinomas (2/2), but not in other types of salivary gland carcinoma (0/46), P<0.00001. By DNA sequencing, genetic alteration of c-kit juxtamembrane domain (exon 11) and tyrosine kinase domain (exon 17) was not found in all the three types of salivary carcinoma that had c-kit protein expression. In conclusion, c-kit protein overexpression is involved in the pathogenesis of certain types of salivary gland carcinoma, but mutation of the gene is not the mechanism of c-kit activation.

Carcinoma, Acinar Cell↗
PubMed2003

Fibroblast growth factor signaling controlling osteoblast differentiation.

Fibroblast growth factors (FGFs) play important roles in skeletal development and postnatal osteogenesis. FGF signaling controls bone formation by regulating the expression of various genes involved in osteoprogenitor cell replication, osteoblast differentiation and apoptosis. Recent genetic manipulation of FGF expression in mice and studies of the phenotype induced by gain-of-function mutations in FGF receptors in humans revealed the important role of FGF signaling in osteoblast function and differentiation. Additionally, cell biology studies allowed to identify some signaling pathways that are involved in the control of FGF actions in osteoblasts. This led to a better understanding of the functional role of FGF signaling in the control of gene expression in osteoblasts. The elucidation of molecular mechanisms by which FGF signaling promotes osteoblast gene expression and differentiation may help to find novel molecular targets and develop new therapeutic approaches to promote bone formation in human bone disorders.

Cell Differentiation↗
PubMed2000

Hyperactivation of the Drosophila Hop jak kinase causes the preferential overexpression of eIF1A transcripts in larval blood cells.

Jak kinase-Stat protein pathways play a critical role in the response of blood cells to a range of cytokines and growth factors. We are using the fruit fly, Drosophila melanogaster, as a model system to elucidate additional components of Jak-Stat pathways, and to determine how abnormalities in this pathway lead to hematopoietic leukemia-like defects. To identify downstream targets, we conducted a molecular screen for genes whose transcripts are overexpressed in response to activation of the Drosophila Hop Jak kinase. We identified a Drosophila homolog of eIF1A, a eukaryotic initiation factor found in humans and other eukaryotes. D-eIF1A is highly overexpressed in the hemocytes and lymph glands of third instar larvae carrying the dominant, gain-of-function mutation hop(Tum-l). A quantitative comparison of poly(A)(+) RNA levels between D-eIF1A and other known Drosophila translation initiation factors indicates that D-eIF1A transcripts preferentially overaccumulate in response to the hyperactive Hop pathway. Our results support the model that D-eIF1A is one of the target genes through which the Drosophila Jak kinase pathway regulates hemocyte development.

Amino Acid Sequence↗
PubMed1997

unc-8, a DEG/ENaC family member, encodes a subunit of a candidate mechanically gated channel that modulates C. elegans locomotion.

Mechanically gated ion channels are important modulators of coordinated movement, yet little is known of their molecular properties. We report that C. elegans unc-8, originally identified by gain-of-function mutations that induce neuronal swelling and severe uncoordination, encodes a DEG/ENaC family member homologous to subunits of a candidate mechanically gated ion channel. unc-8 is expressed in several sensory neurons, interneurons, and motor neurons. unc-8 null mutants exhibit previously unrecognized but striking defects in the amplitude and wavelength of sinusoidal tracks inscribed as they move through an E. coli lawn. We hypothesize that UNC-8 channels could modulate coordinated movement in response to body stretch. del-1, a second DEG/ENaC family member coexpressed with unc-8 in a subset of motor neurons, might also participate in a channel that contributes to nematode proprioception.

Amino Acid Sequence↗
PubMed2003

Screening for effectors that modify multidrug resistance in yeast.

The yeast transcription factors Pdr1p and Pdr3p regulate the expression of several genes that encode energy-dependent efflux pumps involved in multidrug resistance. They recognize specific pleiotropic drug resistance elements in the promoters of the target gene such as PDR5 coding for a major multidrug transporter. Gain-of-function mutations in Pdr1p/Pdr3p result in over-expression of transporter genes and establishment of multidrug resistance. We developed a novel yeast-based screening procedure designed to detect compounds that specifically modify multidrug resistance due to an interference with the expression of drug efflux transporter genes. The screening is based on the ability to abrogate the growth defect of cells suffering from the galactose induced Pdr3p driven over-expression of a dominant-lethal allele of the PMA1 gene placed under the control of the PDR5 promoter. Validation of the assay was achieved by showing that growth inhibition was relieved by mutant Pdr3p devoid of activation domain. This screening system may also be used to select the loss-of-function pdr3 (or pdr1) mutants and to identify specific gene(s) whose over-expression or deletion will suppress the expression of multidrug transporters and increase the susceptibility of yeast cells to antifungals.

Antifungal Agents↗
PubMed2002

Structural basis of von Willebrand factor activation by the snake toxin botrocetin.

The A1 domain of von Willebrand factor (vWF) mediates platelet adhesion to sites of vascular injury by binding to the platelet receptor glycoprotein Ib (GpIb), an interaction that is regulated by hydrodynamic shear forces. The GpIb binding surface of A1 is distinct from a regulatory region, suggesting that ligand binding is controlled allosterically. Here we report the crystal structures of the "gain-of-function" mutant A1 domain (I546V) and its complex with the exogenous activator botrocetin. We show that botrocetin switches the mutant A1 back toward the wild-type conformation, suggesting that affinity is enhanced by augmenting the GpIb binding surface rather than through allosteric control. Functional studies of platelet adhesion under flow further suggest that the activation mechanism is distinct from that of the gain-of-function mutation.

Blood Platelets↗
PubMed2003

Genetics of calcium-sensing--regulation of calcium levels in the body.

The skeleton contains over 200 bones, with the regulation of calcium being vital for maintaining this dynamic tissue. The calcium-sensing receptor (CASR) plays a pivotal role in the regulation of calcium both systemically through the parathyroid and locally in specific tissues. Recent studies have identified several sites of expression and further functions for the CASR gene, which include a role in the epidermis, tooth development and fluid regulation. In addition, genetic studies have identified gain-of-function mutations in the CASR gene, leading to a greater understanding of the pathogenesis of Bartter's syndrome, an inherited nephropathy that results in deficiency of sodium and chloride absorption.

Bartter Syndrome↗
PubMed2004

Cryptic bracts exposed: insights into the regulation of leaf expansion.

Arabidopsis is unusual in producing flowers that are not subtended by specialized leaves, called floral bracts. Writing in Development, Dinneny et al. and Ohno et al. show that gain-of-function mutations of the JAGGED transcription factor produce bracts, and provide evidence that this gene plays a key role in a developmental program that regulates the size and shape of all leaves and leaf-homologs.

Arabidopsis↗
PubMed2001

Spatial and temporal gene expression for fibroblast growth factor type I receptor (FGFR1) during fracture healing in the rat.

Recent experiments have shown that exogenous basic fibroblast growth factor (bFGF) enlarges fracture callus and accelerates the healing of osteotomized long bones. The actions of bFGF are mediated by four different transmembrane receptors (FGFR1-4). Among them, FGFR1 has a high affinity for bFGF, and gain-of-function mutations of the FGFR1 gene cause craniosynostosis in humans. Gene expression for FGFR1 has been analyzed in embryogenesis; however, in skeletal repair, detailed expression of FGFR1 has not been fully established. In the present study, a rat model of closed femoral fracture healing was used to quantify mRNA encoding the FGFR1 and to characterize cells expressing FGFR1 by in situ hybridization. Gene expression for FGFR1 was rapidly upregulated after fracture; its mRNA level on day 1 was 3.4-fold higher than that of unfractured femora. At this stage, a moderate signal for FGFR1 was detected in periosteal osteoprogenitor cells, inflammatory cells near fracture sites, and cells among muscle layers. FGFR1 mRNA reached peak expression when callus remodeling actively progressed (6.8-fold on day 14), and remained elevated even in the later stages of healing (6.3-fold on day 28). During the intermediate stage of fracture healing, a strong signal for FGFR1 was diffusely distributed in mature osteoblasts in the hard callus, and mature osteoclasts also expressed a weak signal for FGFR1. These results suggest that FGF/FGFR1 signaling has multifunctional roles during fracture healing and may regulate both osteoblasts and osteoclasts, contributing to bone formation and callus remodeling.

Animals↗
PubMed1996

Doublefoot: a new mouse mutant affecting development of limbs and head.

The mutant doublefoot, Dbf, of the mouse arose spontaneously, and was shown to be inherited as an autosomal dominant, mapping 9-13 cM proximal to leaden, In, on chromosome 1 and showing no recombination with the microsatellite markers D1Mit24 and D1Mit77. In heterozygotes the phenotype includes many extra toes on all four feet, and the tibia and fibula may be reduced and bowed. The head is shortened and broad and the eyes are held half-closed, and some animals develop hydrocephalus. The tail is kinked and abnormally thick, and the soles of the feet are swollen. Growth is retarded, viability is reduced, and reproduction is impaired in both sexes. Only about 30% of males are normally fertile, and testis weights and sperm counts may be reduced, although this appears not to be the main cause of poor fertility. In females vaginal opening is delayed and oestrous cycles are irregular, although the animals appear to respond to gonadotrophic hormones. Crosses of Dbf/+ x Dbf/+ are very poorly fertile. Prenatally, Dbf/+ heterozygotes can first be recognized at 11 1/2 days gestation by abnormally broad fore limb buds. Putative Dbf/Dbf homozygotes at 12 1/2 days have similar limbs defects and also split face, due to failure of the maxillae to fuse in the midline. Some homozygotes and a few putative heterozygotes have cranioschisis. At 13 1/2 days, the heads of homozygotes tend to bulge in the frontal region and a bleb of clear fluid is visible medially. At 14 1/2 days Dbf/Dbf fetuses may have oedema and some are dead. From 15 1/2 days onwards no live Dbf/Dbf fetuses have been found. The gene maps close to the locus of Pax3, but crossovers between Dbf and Pax3 have been found, ruling out the possibility that a gain-of-function mutation in Pax3 might be involved.

Animals↗