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PubMed2004

Signal transduction via the stem cell factor receptor/c-Kit.

Together with its ligand, stem cell factor, the receptor tyrosine kinase c-Kit is a key controlling receptor for a number of cell types, including hematopoietic stem cells, mast cells, melanocytes and germ cells. Gain-of-function mutations in c-Kit have been described in a number of human cancers, including testicular germinomas, acute myeloid leukemia and gastrointestinal stromal tumors. Stimulation of c-Kit by its ligand leads to dimerization of receptors, activation of its intrinsic tyrosine kinase activity and phosphorylation of key tyrosine residues within the receptor. These phosphorylated tyrosine residues serve as docking sites for a number of signal transduction molecules containing Src homology 2 domains, which will thereby be recruited to the receptor and activated many times through phosphorylation by the receptor. This review discusses our current knowledge of signal transduction molecules and signal transduction pathways activated by c-Kit and how their activation can be connected to the physiological outcome of c-Kit signaling.

Alternative Splicing↗
PubMed2006

[Surgical considerations for gastrointestinal stroma tumor].

Gastrointestinal stroma tumors (GIST), an abdominal stroma entity, are characterized by a gain-in-function mutation in the c-kit proto-oncogen (CD117). Initial treatment should aim at complete removal of the primary tumor (R0 resection), which almost never develops lymphatic metastases. Distant metastatic spread mainly involves the peritoneal cavity and the liver. In patients with metastatic disease, treatment with the tyrosine kinase inhibitor imatinib mesylate is indicated and very effective. Systemic chemotherapy and external beam radiation must be considered ineffective. Patients requiring multivisceral resection for primary tumor removal quickly develop tumor recurrence and could benefit from preoperative treatment with imatinib. To assess the response to treatment, 18F-FDG positron emission tomography or gadolinium-enhanced magnetic resonance imaging have proven helpful, as the conventional criteria of tumor shrinkage according to WHO standards are rarely met. Primary tumors are classified into four risk categories according to size and mitotic activity. The possible advantages of adjuvant treatment are currently under investigation through international randomized trials. Patients who develop extensive remission of metastatic disease should be evaluated individually for resection of the tumor remnants. Even the resection of single progressive lesions (newly developed mutations) should be considered in carefully selected patients if the remaining tumor can be controlled by continued imatinib treatment.

Antigens, CD34↗
PubMed2001

FLT3 tyrosine kinase as a target molecule for selective antileukemia therapy.

Fusion gene products such as PML-RARalpha and BCR-ABL generated by leukemia-specific chromosomal translocations have been identified as target molecules for the treatment of leukemia. Here we describe one possibility for extending the frontier of mechanism-based medicine for acute myeloid leukemia (AML). FLT3, a receptor tyrosine kinase (RTK) preferentially expressed in hematopoietic progenitor cells, frequently has a gain-of-function mutation in AML. To search for FLT3-targeted compounds, we screened the growth-inhibitory effects of several tyrosine kinase inhibitors (TKIs) on mutant FLT3-transformed 32D cells. Herbimycin A at a concentration of 0.1 microM markedly inhibited the growth of the transfectants but at that concentration was ineffective in parental 32D cells. It suppressed the constitutive tyrosine phosphorylation of the mutant FLT3, but not the phosphorylation of the ligand-stimulated wild-type FLT3. In mice transplanted with transformed 32D cells, the administration of herbimycin A completely prevented leukemia progression. Recent studies have indicated that herbimycin A binds directly with HSP90, a molecular chaperone, and destabilizes HSP90-associated proteins. Another HSP90 inhibitor, radicicol, also induced apoptosis selectively in transformed 32D cells. HSP90 is a promising target for the treatment of AML with mutant FLT3.

Acute Disease↗
PubMed2006

Polymorphisms in the IL-13 and IL-4 receptor alpha genes and allergic rhinitis.

The IL-4 receptor (IL-4R) and IL-13 genes are candidate genes in atopic diseases. The IL-4Ralpha chain and IL-13 promoter polymorphisms are gain-of-function mutations associated with atopy. We tested whether polymorphisms in the IL-4Ralpha chain and the coding region of the IL-13 gene are associated with allergic rhinitis in a Korean population. Polymerase chain reaction-based assays for IL-4Ralpha Gln551Arg and IL-13 exon 4 G2044A were used for genotyping. There were no differences in the frequencies of the genotypes and alleles of IL-4Ralpha between the controls and patients. The frequency of the IL-13 exon 4 2044A allele was statistically different between the controls and patients. Our results suggest that the IL-13 exon 4 G2044A polymorphism confers susceptibility to the development of allergic rhinitis in Koreans, whereas the IL-4Ralpha Gln551Arg polymorphism is not related to allergic rhinitis.

Adult↗
PubMed2003

Extracellular Na+ removal attenuates rundown of the epithelial Na+-channel (ENaC) by reducing the rate of channel retrieval.

Regulation of the epithelial sodium channel (ENaC) is important for the long-term control of arterial blood pressure as evidenced by gain of function mutations of ENaC causing Liddle's syndrome, a rare form of hereditary arterial hypertension. In Xenopus laevis oocytes expressing ENaC a spontaneous decline of ENaC currents over time, so-called rundown, is commonly observed. Mechanisms involved in rundown may be physiologically relevant and may be related to feedback regulation of ENaC by intra- or extracellular Na+. We tested the effect of extracellular Na+ removal on ENaC rundown. Spontaneous rundown of ENaC was largely prevented by extracellular Na+ removal and was partially prevented by primaquine suggesting that it is due to endocytic channel retrieval. Liddle's syndrome mutation caused a reduced rate of rundown, and in oocytes expressing the mutated channel extracellular Na+ removal not only prevented rundown but even increased the ENaC currents (runup). Acute exposure to high extracellular Na+ drastically reduced whole-cell currents and surface expression of wild-type ENaC, while these effects were much smaller in ENaC with Liddle's syndrome mutation consistent with a stabilization of the mutated channel in the plasma membrane. Interestingly, the apparent intracellular Na+ concentration [Na+](i-app) was high (>60 mM) in ENaC-expressing oocytes but rundown was not associated with a further increase in [Na+](i-app). We conclude that the inhibitory effect of extracellular Na+ removal on rundown is due to an inhibition of endocytic ENaC retrieval.

Animals↗
PubMed2005

tantalus, a potential link between Notch signalling and chromatin-remodelling complexes.

The tantalus (tan) gene encodes a protein that interacts specifically with the Polycomb/trithorax group protein Additional sex combs (ASX). Both loss-of-function and gain-of-function mutations in tan cause tissue-specific defects in the eyes, wing veins and bristles of adult flies. As these defects are also typical for components of the Notch (N) signalling pathway, we wished to determine if TAN interacts with this pathway. Through careful examination of ectopic tan phenotypes, we find that TAN specifically disrupts all three major processes associated with the N signalling pathway (boundary formation, lateral inhibition, and lineage decisions). Furthermore, ectopic tan expression abolishes expression of two N target genes, wingless (wg) and cut, at the dorsal-ventral boundary of the wing. An interaction between tan and N was also observed using a genetic assay that previously detected interactions between tan and Asx. The previously observed ability of TAN to move between the cytoplasm and nucleus, and to associate with DNA, provides a potential mechanism for TAN to respond to N signalling.

Animals↗
PubMed1999

Snail-type zinc finger proteins prevent neurogenesis in Scutoid and transgenic animals of Drosophila.

Scutoid is a classical dominant gain-of-function mutation of Drosophila, causing a loss of bristles and roughening of the compound eye. Previous genetic and molecular analyses have shown that Scutoid is associated with a chromosomal transposition resulting in a fusion of no-oceli and snail genes. How this gene fusion event leads to the defects in neurogenesis was not known until now. Here have found that snail is ectopically expressed in the eye-antennal and wing imaginal discs in Scutoid larvae, and that this expression is reduced in Scutoid revertants. We have also shown that the expressivity of Scutoid is enhanced by zeste mutations. snail and escargot encode evolutionarily conserved zinc-finger proteins involved in the development of mesoderm and limbs. Snail and Escargot proteins share a common target DNA sequence with the basic helix-loop-helix (bHLH) type proneural gene products. When expressed in the developing external sense organ precursors of the thorax and the eye, these proteins cause a loss of mechanosensory bristles in the thorax and perturbed the development of the compound eye. Such phenotypes resemble those associated with Scutoid. Furthermore, the effect of ectopic Escargot on bristle development is antagonized by coexpression of the bHLH gene asense. Thus, our results suggest that the Scutoid phenotype is due to an ectopic snail expression under the control of no-oceli enhancer, antagonizing neurogenesis through its inhibitory interaction with bHLH proteins.

Animals↗
PubMed1998

Predicting response to cancer chemotherapy: the role of p53.

Loss of wild-type p53 activity is thought to be a major predictor of failure to respond to radiotherapy and chemotherapy in various human cancers. This assumption is largely based on some cell-death studies in p53-knockout mice and on correlations of p53 status assessed by immunochemistry or single-strand conformational polymorphism (SSCP) analysis, and responses to therapy in human cancers in vivo. In principle, p53 may enhance chemosensitivity by promoting apoptosis via transcription-independent mechanisms as well as transcriptional activation of proapoptotic genes such as bax and transcriptional repression of antiapoptotic genes such as bcl-2. Drug-induced suicide mediated by the CD95/CD95 ligand system may also involve a p53-controlled pathway. Yet, p53 may decrease chemosensitivity by promoting p21-mediated and p21-independent growth arrest, DNA repair, and differentiation, and by enhancing the transcription of antiapoptotic genes such as bcl-x. Cell-culture work indicates that the effects of altering the p53 status on chemosensitivity depend very much on the cellular context. Disruption of p53 function in otherwise normal, nonneoplastic cells may enhance rather than decrease chemosensitivity. However, targeted p53 gene disruption in some cell types obtained from p53-knockout mice results in enhanced rather than decreased sensitivity, e.g., to irradiation. Transformed cells that have retained wild-type p53 function tend to acquire chemoresistance when p53 function is disabled, with few exceptions. Thus, preexisting molecular alterations or consecutive accumulation of molecular alterations after loss of p53 rather than the loss of wild-type p53 activity per se may confer chemoresistence to tumor cells. Moreover, p53 accumulation resulting from the increased half-life of mutant p53 proteins can act as a gain-of-function mutation, presumably as a consequence of multiple protein-protein interactions. Finally, significant tumor cell-type- and drug-specific patterns of modulation of chemosensitivity by p53 are beginning to emerge. Transfer of wild-type p53 genes into tumor cells commonly induces growth arrest but may render these cells relatively more resistant to most chemotherapeutic drugs. Therefore, careful experimental in vitro and in vivo studies are required before chemotherapy-supported p53 gene therapy for human cancer is introduced into clinical practice.

Animals↗
PubMed2005

Coat protein-independent cell-to-cell movement of bromoviruses expressing brome mosaic virus movement protein with an adaptation-related amino acid change in the central region.

The movement protein (MP) of Brome mosaic virus (BMV) depends on the coat protein (CP) to mediate the cell-to-cell movement of BMV and CCMV(B3a), a recombinant Cowpea chlorotic mottle virus (CCMV) expressing BMV MP. Previous studies identified gain-of-function mutations in the central region of BMV MP that enable CCMV(B3a) to adapt to a resistant host. This study demonstrates that all adaptation-related MPs can partially or almost fully mediate the cell-to-cell movement of CCMV(B3a) and BMV without CP. Based on these results, we discuss adaptation mechanisms of CCMV(B3a) and the role of the central region of MP in the determination of virus movement mode.

Adaptation, Physiological↗
PubMed2004

Differential protein expression profile in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal through gain of function mutations of the oncogene KIT. Imatinib offers the first effective treatment for patients with GISTs, but the therapeutic outcome strongly depends on the type of KIT mutation. We used ProteinChip technology to investigate whether GISTs with different KIT mutations express different proteins. In total, 154 proteins were significantly differentially expressed in GISTs with exon 9 KIT mutation compared to GISTs with exon 11 KIT mutation.

Exons↗
PubMed2004

The epithelial sodium channel: from molecule to disease.

Genetic analysis has demonstrated that Na absorption in the aldosterone-sensitive distal nephron (ASDN) critically determines extracellular blood volume and blood pressure variations. The epithelial sodium channel (ENaC) represents the main transport pathway for Na+ absorption in the ASDN, in particular in the connecting tubule (CNT), which shows the highest capacity for ENaC-mediated Na+ absorption. Gain-of-function mutations of ENaC causing hypertension target an intracellular proline-rich sequence involved in the control of ENaC activity at the cell surface. In animal models, these ENaC mutations exacerbate Na+ transport in response to aldosterone, an effect that likely plays an important role in the development of volume expansion and hypertension. Recent studies of the functional consequences of mutations in genes controlling Na+ absorption in the ASDN provide a new understanding of the molecular and cellular mechanisms underlying the pathogenesis of salt-sensitive hypertension.

Aldosterone↗
PubMed2006

HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53.

HAMLET (Human alpha-lactalbumin Made Lethal to Tumor cells) triggers selective tumor cell death in vitro and limits tumor progression in vivo. Dying cells show features of apoptosis but it is not clear if the apoptotic response explains tumor cell death. This study examined the contribution of apoptosis to cell death in response to HAMLET. Apoptotic changes like caspase activation, phosphatidyl serine externalization, chromatin condensation were detected in HAMLET-treated tumor cells, but caspase inhibition or Bcl-2 over-expression did not prolong cell survival and the caspase response was Bcl-2 independent. HAMLET translocates to the nuclei and binds directly to chromatin, but the death response was unrelated to the p53 status of the tumor cells. p53 deletions or gain of function mutations did not influence the HAMLET sensitivity of tumor cells. Chromatin condensation was partly caspase dependent, but apoptosis-like marginalization of chromatin was also observed. The results show that tumor cell death in response to HAMLET is independent of caspases, p53 and Bcl-2 even though HAMLET activates an apoptotic response. The use of other cell death pathways allows HAMLET to successfully circumvent fundamental anti-apoptotic strategies that are present in many tumor cells.

Animals↗
PubMed2005

A case of hyperinsulinism/hyperammonaemia syndrome with reduced carbamoyl-phosphate synthetase-1 activity in liver: a pitfall in enzymatic diagnosis for hyperammonaemia.

We report a patient who was first diagnosed as having congenital carbamoyl-phosphate synthetase-1 (CPS-1) deficiency on the basis of significantly low CPS-1 activity in the liver at 1 year of age. We then started therapy against hyperammonaemia with little effect and, at the age of 15 years, we analysed the GLUD1 gene and found a previously reported gain-of-function mutation in the gene, resulting in a change of her diagnosis to hyperinsulinism/hyperammonaemia (HI/HA) syndrome. This case demonstrates that low CPS-1 activity in liver, however significant it might be, does not always come from a primary CPS-1 deficiency and that we have to take into consideration the possibility of a secondary CPS-1 deficiency, such as HI/HA syndrome.

Adolescent↗
PubMed2005

Molecular research directions in the management of gastrointestinal stromal tumors.

Imatinib mesylate (STI571) is an oral 2-phenylaminopyrimidine derivative that acts as a selective inhibitor against several receptor tyrosine kinases and has been viewed as one of the therapeutic success stories of the 21st century. Imatinib was first shown to inhibit the causative molecular translocation in chronic myelogenous leukemia, BCR-ABL. Because imatinib could also inhibit the activity of KIT, a 145-kD transmembrane glycoprotein, and because gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the digestive tract, are characterized by expression of a gain-of-function mutation in KIT, imatinib was used in therapeutic trials of GISTs beginning in 1999. The initial success has now resulted in more widespread use of imatinib for the treatment of patients with GIST. Molecular genetic studies have shown that most GISTs possess a KIT mutation in exon 9, 11, 13, or 17. Clinically, GIST patients with KIT exon 11 mutations (ie, the juxtamembrane region) are the most prevalent and sensitive to imatinib. In addition to the inhibitory effect on KIT, imatinib also inhibits the activity of mutant platelet-derived growth factor receptor-alpha (PDGFRalpha) found in a subset of GIST. What is becoming evident is that there are patients with GIST who lack mutations in KIT or PDGFRalpha, or possess "imatinib-resistant" mutations (such as exon 17 mutations in KIT and exon 18 mutations in PDGFRalpha). These patients typically do not respond well to imatinib therapy. Therefore, identifying additional genetic factors that contribute to the pathogenesis of GIST, independent of KIT and PDGFRalpha, will be important in developing additional anti-GIST therapies. As one might suspect from previous experiences with antitumor therapies, primary and secondary resistance to imatinib is also becoming a major clinical problem in the treatment of this disease. Therefore, new drugs that can serve as alternative therapies in imatinib-resistant patients with GIST or that can be used in combination with imatinib will be needed. As with most recent efforts to derive novel molecular target therapies to treat cancer, improved therapy of GIST will continue to benefit from advances in the molecular characterization of this disease.

Antineoplastic Agents↗
PubMed1987

The enhancer of split locus and neurogenesis in Drosophila melanogaster.

Enhancer of split (E(spl)) is one of a group of so-called neurogenic genes of Drosophila. We describe two different types of E(spl) alleles, dominant and recessive, which exert opposite effects on both central and peripheral nervous system development. The only extant dominant allele determines a reduction in the number of central neurons and peripheral sensilla; this phenotype is not reduced by a normal complement of wild-type alleles. Since animals carrying a triploidy for the wild-type locus develop similar defects, the dominant allele is probably the result of a gain-of-function mutation. Several recessive alleles, obtained as revertants of the dominant allele, are loss-of-function mutations and determine considerable neural hyperplasia. The present evidence suggests that neural defects of E(spl) mutants are due to defective segregation of neural and epidermal lineages, leading to neural commitment of less or of more cells than in the wild type, depending upon whether the animals carry the dominant or any of the recessive alleles, respectively. Therefore, E(spl) formally behaves as a gene switching between neural and epidermal pathways.

Alleles↗
PubMed1993

Translational regulation of tra-2 by its 3' untranslated region controls sexual identity in C. elegans.

C. elegans hermaphrodites make sperm and then oocytes in an otherwise female animal. Gain-of-function mutations in the sex-determining gene tra-2 (tra-2(gf)) transform hermaphrodites into females (spermless hermaphrodites). The tra-2(gf) mutations map to a perfect direct repeat in the 3' untranslated region; each repeat is called a direct repeat element (DRE). Three experiments demonstrate that DREs repress tra-2 at the translational level. First, tra-2(gf) mRNAs are associated with larger polysomes than are their wild-type counterparts. Second, translation of a reporter RNA is inhibited by DREs. Third, disruption of DREs does not increase tra-2 mRNA levels. An RNA binding activity specifically associates with the DREs. We propose that tra-2 translation is inhibited by association of an RNA binding-factor with the DREs and that this translational control is essential for development of C. elegans as a hermaphrodite/male species.

Animals↗
PubMed1995

Malformations of the heart, kidney, palate, and skeleton in alpha-MHC-Hoxb-7 transgenic mice.

To begin to define the genetic network involved in cardiogenesis, we generated mice bearing the alpha-myosin heavy chain (MHC)-Hoxb-7 transgene. We hypothesized that using the cardiac-specific alpha-MHC promoter, we can direct ectopic expression of Hoxb-7 in the heart and perturb its normal development. Both whole mount in situ hybridization and northern analyses showed that this alpha-MHC promoter resulted in transgene expression in the developing heart. Severe ventricular septal defects (VSD) were found in several mutant mice. Interestingly, transgenic mice were observed to have other malformations as well, including cleft palate, renal anomalies, and skeletal abnormalities in the craniocervical and costosternal regions. The kidney defect consisted of double ureter and pelvis. In summary, we have shown that a dominant gain-of-function mutation of Hoxb-7 using the murine alpha-MHC promoter results in perturbation of the genetic circuitry underlying multiple developmental processes, including cardiogenesis. Misexpression of Hoxb-7 during heart development may be involved in the pathogenesis of VSD.

Aging↗
PubMed2005

Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor.

Signaling by stem cell factor and Kit, its receptor, plays important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Deficiencies of either produce defects in red and white blood cell production, hypopigmentation, and sterility. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, and mastocytomas. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. The adaptor protein APS, Src family kinases, and Shp2 tyrosyl phosphatase bind to phosphotyrosine 568. Shp1 tyrosyl phosphatase and the adaptor protein Shc bind to phosphotyrosine 570. C-terminal Src kinase homologous kinase and the adaptor Shc bind to both phosphotyrosines 568 and 570. These residues occur in the juxtamembrane segment of Kit. Three residues in the kinase insert domain are phosphorylated and attract the adaptor protein Grb2 (Tyr703), phosphatidylinositol 3-kinase (Tyr721), and phospholipase Cgamma (Tyr730). Phosphotyrosine 900 in the distal kinase domain binds phosphatidylinositol 3-kinase which in turn binds the adaptor protein Crk. Phosphotyrosine 936, also in the distal kinase domain, binds the adaptor proteins APS, Grb2, and Grb7. Kit has the potential to participate in multiple signal transduction pathways as a result of interaction with several enzymes and adaptor proteins.

Adaptor Proteins, Signal Transducing↗