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1.
Oncogenic protein tyrosine kinases 总被引:8,自引:0,他引:8
Platelet-derived growth factor receptors (PDGFRs) and their ligands, platelet-derived growth factors (PDGFs) play critical roles in mesenchymal cell migration and proliferation. In embryogenesis the PDGFR/PDGF system is essential for the correct development of the kidney, cardiovascular system, brain, lung and connective tissue. In adults, PDGFR/PDGF is important in wound healing, inflammation and angiogenesis. Abnormalities of PDGFR/PDGF are thought to contribute to a number of human diseases, and especially malignancy. Constitutive activation of the PDGFRalpha or PDGFRbeta receptor tyrosine kinases is seen in myeloid malignancies as a consequence of fusion to diverse partner genes, and activating mutations of PDGFRalpha are seen in gastrointestinal tumours (GISTs). Autocrine signalling as a consequence of PDGF-B overexpression is clearly implicated in the pathogenesis of dermatofibrosarcoma protruberans (DFSP) and overexpression of PDGFRs and/or their ligands has been described in many solid tumours. PDGFR signalling is inhibited by imatinib mesylate, and this compound has clear clinical activity in patients with myeloid malignancies, GIST and DFSP. 相似文献
2.
Wong RW 《Cellular and molecular life sciences : CMLS》2003,60(1):113-118
Generation of genetically engineered mice with either gain-of-function or loss-of-function mutations is the most popular
technique for determining gene functions and the interrelationship between molecules in vivo. These models have provided a
wealth of information about the developmental and physiological roles of oncogenes and growth factors. To date, transgenic
techniques have been used extensively to study the functions of the epidermal growth factor (EGF) family. This review highlights
some of the major recent findings pertinent to the EGF receptor (EGFR) and its ligands with special reference to elucidating
how EGF and its related growth factors work together to regulate reproduction, growth and development. Finally, future investigations
on ligand-ligand communications, EGFR and its ligands in neural stem cell research, and the mechanisms of EGFR signaling and
trafficking in cells are also suggested.
Received 24 May 2002; received after revision 15 July 2002; accepted 16 July 2002 相似文献
3.
Signal transduction via the stem cell factor receptor/c-Kit 总被引:6,自引:0,他引:6
Rönnstrand L 《Cellular and molecular life sciences : CMLS》2004,61(19-20):2535-2548
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. 相似文献
4.
Krassimira Angelova Angelo Felline Moon Lee Manish Patel David Puett Francesca Fanelli 《Cellular and molecular life sciences : CMLS》2011,68(7):1227-1239
The luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) particularly susceptible to spontaneous pathogenic
gain-of-function mutations. Protein structure network (PSN) analysis on wild-type LHR and two constitutively active mutants,
combined with in vitro mutational analysis, served to identify key amino acids that are part of the regulatory network responsible
for propagating communication between the extracellular and intracellular poles of the receptor. Highly conserved amino acids
in the rhodopsin family GPCRs participate in the protein structural stability as network hubs in both the inactive and active
states. Moreover, they behave as the most recurrent nodes in the communication paths between the extracellular and intracellular
sides in both functional states with emphasis on the active one. In this respect, non-conservative loss-of-function mutations
of these amino acids is expected to impair the most relevant way of communication between activating mutation sites or hormone-binding
domain and G protein recognition regions. 相似文献
5.
Kopp P 《Cellular and molecular life sciences : CMLS》2001,58(9):1301-1322
The thyrotropin (TSH) receptor plays a preeminent role in thyroid physiology and disease. TSH, acting through the TSH receptor,
is the major stimulator of thyroid cell growth, differentiation and function. In Graves' disease, the TSH receptor is the
target of stimulating antibodies that cause hyperthyroidism. Although still a topic of debate, the TSH receptor has been implicated
in the pathogenesis of the endocrine ophthalmopathy associated with Graves' disease. Blocking antibodies against the TSH receptor
are involved in the development of hypothyroidism in a subset of patients with autoimmune hypothyroidism. Transplacental passage
of stimulating or blocking TSH receptor antibodies from a mother with autoimmune thyroid disease may result in transient hyper-
or hypothyroidism in early infancy. During pregnancy, the placental hormone human choriogonadotropin (hCG) can cause gestational
hyperthyroidism through cross-reaction with the TSH receptor. Gestational hyperthyroidism may also be involved in the pathogenesis
of hyperemesis gravidarum. Trophoblast tumors secreting hCG are a rare cause of hyperthyroidism. Somatic activating mutations
of the TSH receptor have been identified as a molecular cause of toxic adenomas, whereas activating mutations in the germline
give rise to nonautoimmune familial hyperthyroidism or sporadic congenital hyperthyroidism. These gain-of-function mutations
are dominant, and one mutated allele is sufficient to result in disease. Inactivating germline mutations of both TSH receptor
alleles lead to variable degrees of resistance to TSH, encompassing a spectrum ranging from euthyroid hyperthyrotropinemia
to overt hypothyroidism with thyroid hypoplasia.
Received 31 January 2001; received after revision 3 April 2001; accepted 3 April 2001 相似文献
6.
Rare human primary immunodeficiency disorders with extreme susceptibility to infections in infancy have provided important insights into immune function. Increasingly, however, primary immunodeficiencies are also recognized as a cause of other more common, often discrete, infectious susceptibilities. In a wider context, loss-of-function mutations in immune genes may also cause disorders of immune regulation and predispose to cancer. Here, we review the associations between human diseases and mutations in genetic elements affecting natural killer (NK) cell development and function. Although many such genetic aberrations significantly reduce NK cell numbers or severely impair NK cell responses, inferences regarding the role of NK cells in disease are confounded by the fact that most mutations also affect the development or function of other cell types. Still, data suggest an important role for NK cells in diseases ranging from classical immunodeficiency syndromes with susceptibility to viruses and other intracellular pathogens to cancer, autoimmunity, and hypersensitivity reactions. 相似文献
7.
R. M. Shuman 《Cellular and molecular life sciences : CMLS》1991,47(9):897-905
The avian embryo presents a tremendous challenge for those interested in accessing and manipulating the avian germ line. By far the most successful method of gene transfer is by retrovirus vector. The efficacy of retrovirus vectors has been demonstrated by germ line insertion of replication-competent retroviruses as well as the insertion of replication-defective retrovirus vectors carrying bacterial marker genes. Retroviral vectors have also been shown to be useful for the transfer and expression of genes in somatic cells. Further, germ line transgenesis has been reported in both the chicken and the Japanese quail. In addition, several alternative gene transfer methods are under development. These include transfection of avian sperm, development of germ line chimeras using primordial germ cells and blastodermal cells, and the development of embryonic stem cell lines. Potentially, basic research and the poultry industry will derive substantial benefit from this revolutionary technology. 相似文献
8.
Production of transgenic birds 总被引:1,自引:0,他引:1
R M Shuman 《Experientia》1991,47(9):897-905
The avian embryo presents a tremendous challenge for those interested in accessing and manipulating the avian germ line. By far the most successful method of gene transfer is by retrovirus vector. The efficacy of retrovirus vectors has been demonstrated by germ line insertion of replication-competent retroviruses as well as the insertion of replication-defective retrovirus vectors carrying bacterial marker genes. Retroviral vectors have also been shown to be useful for the transfer and expression of genes in somatic cells. Further, germ line transgenesis has been reported in both the chicken and the Japanese quail. In addition, several alternative gene transfer methods are under development. These include transfection of avian sperm, development of germ line chimeras using primordial germ cells and blastodermal cells, and the development of embryonic stem cell lines. Potentially, basic research and the poultry industry will derive substantial benefit from this revolutionary technology. 相似文献
9.
Marco G. Alves Luís Rato Rui A. Carvalho Paula I. Moreira Sílvia Socorro Pedro F. Oliveira 《Cellular and molecular life sciences : CMLS》2013,70(5):777-793
Hormonal regulation is essential to spermatogenesis. Sertoli cells (SCs) have functions that reach far beyond the physical support of germ cells, as they are responsible for creating the adequate ionic and metabolic environment for germ cell development. Thus, much attention has been given to the metabolic functioning of SCs. During spermatogenesis, germ cells are provided with suitable metabolic substrates, in a set of events mediated by SCs. Multiple signaling cascades regulate SC function and several of these signaling pathways are hormone-dependent and cell-specific. Within the seminiferous tubules, only SCs possess receptors for some hormones rendering them major targets for the hormonal signaling that regulates spermatogenesis. Although the mechanisms by which SCs fulfill their own and germ cells metabolic needs are mostly studied in vitro, SC metabolism is unquestionably a regulation point for germ cell development and the hormonal control of these processes is required for a normal spermatogenesis. 相似文献
10.
B. Iyengar 《Cellular and molecular life sciences : CMLS》1982,38(10):1239-1240
Summary This study is based on 100 consecutive germ cell tumors of the gonads, received during a 5-year period. Benign teratomas, with totipotent differentiation are the commonest ovarian germ cell tumors, whereas the nullipotent germinomas from the bulk of the testicular tumors. Differentiation in the rapidly proliferating testicular teratomas, occurs in the form of embryoid bodies and organoid structures. From an analysis of the germ cell tumors it is evident that the ovum confers differentiating functions on the zygote, while the spermatozoon confers functions of organization and proliferation. This difference in the behavior of the 2 germ cells is due to local feedbacks within the cortical and medullary zones of the gonads.Acknowledgments. I wish to thank Dr S. K. Lal, Maulana Azad Medical College, New Delhi, for his valuable suggestions concerning gonadal functions. Reprint requests to B. I., B-72, Pandara Road, New Delhi-110003 (India). 相似文献
11.
Tauzin S Debure L Moreau JF Legembre P 《Cellular and molecular life sciences : CMLS》2012,69(8):1261-1277
Apoptosis has emerged as a fundamental process important in tissue homeostasis, immune response, and during development. CD95
(also known as Fas), a member of the tumor necrosis factor receptor (TNF-R) superfamily, has been initially cloned as a death
receptor. Its cognate ligand, CD95L, is mainly found at the plasma membrane of activated T-lymphocytes and natural killer
cells where it contributes to the elimination of transformed and infected cells. According to its implication in the immune
homeostasis and immune surveillance, and since several malignant cells of various histological origins exhibit loss-of-function
mutations, which cause resistance towards the CD95-mediated apoptotic signal, CD95 has been classified as a tumor suppressor
gene. Nevertheless, this assumption has been recently challenged, as in certain pathophysiological contexts, CD95 engagement
transmits non-apoptotic signals that promote inflammation, carcinogenesis or liver/peripheral nerve regeneration. The focus
of this review is to discuss these apparent contradictions of the known function(s) of CD95. 相似文献
12.
Germline development in vertebrates and invertebrates 总被引:13,自引:0,他引:13
In all animals information is passed from parent to offspring via the germline, which segregates from the soma early in development
and undergoes a complex developmental program to give rise to the adult gametes. Many aspects of germline development have
been conserved throughout the animal kingdom. Here we review the unique properties of germ cells, the initial determination
of germ cell fates, the maintenance of germ cell identity, the migration of germ cells to the somatic gonadal primordia and
the proliferation of germ cells during development in vertebrates and invertebrates. Similarities in germline development
in such diverse organisms as Drosophila melanogaster, Caenorhabditis elegans, Xenopus laevis and Mus musculus will be highlighted.
Received 11 December 1998; received after revision 25 January 1999; accepted 25 January 1999 相似文献
13.
Biological implications of preformed mast cell mediators 总被引:1,自引:0,他引:1
Mast cells store an impressive array of preformed compounds (mediators) in their secretory granules. When mast cells degranulate,
these are released and have a profound impact on any condition in which mast cell degranulation occurs. The preformed mast
cell mediators include well-known substances such as histamine, proteoglycans, proteases, and preformed cytokines, as well
as several recently identified compounds. Mast cells have recently been implicated in a large number of novel pathological
settings in addition to their well-established contribution to allergic reactions, and there is consequently a large current
interest in the molecular mechanisms by which mast cells act in the context of a given condition. In many cases, preformed
mast cell mediators have been shown to account for functions ascribed to mast cells, and these compounds are hence emerging
as major players in numerous pathologies. In this review we summarize the current knowledge of preformed mast cell mediators. 相似文献
14.
Neurotrophins are a family of structurally and functionally related neurotrophic factors which, in mammals, include: nerve
growth factor, brain-derived neurotrophic factor, neurotrophin-3 (NT-3), and NT-4/5. In addition to their canonical role in
promoting neuronal survival, these molecules appear to regulate multiple aspects of the development of the nervous system
in vertebrates, including neuronal differentiation, axon elongation and target innervation, among others. Actions of neurotrophins
and of their receptors in vivo are being analyzed by loss-of-function or gain-of-function experiments in mice. Here, we review
the phenotypes of the primary sensory system in these mutant mouse strains and the different strategies specifically involved
in the regulation of neuronal survival by neurotrophins in this portion of the nervous system.
Received 10 December 2001; received after revision 11 May 2002; accepted 13 May 2002
RID="*"
ID="*"Corresponding author. 相似文献
15.
Matin A 《Cellular and molecular life sciences : CMLS》2007,64(11):1317-1322
The 129 mouse strain develops congenital testicular germ cell tumors (TGCTs) at a low frequency. TGCTs in mice resemble the
testicular tumors (teratomas) that occur in human infants. The genes that cause these tumors in 129 have not been identified.
The defect at the Ter locus increases TGCT incidence such that 94% of 129-Ter/Ter males develop TGCTs. The primary effect of the Ter mutation is progressive loss of primordial germ cells (PGCs) during embryonic development. This results in sterility in adult
Ter/Ter mice on all mouse strain backgrounds. However, on the 129 background, Ter causes tumor development in addition to sterility. Therefore, Ter acts as a modifier of 129-derived TGCT susceptibility genes. Ter was identified to be a mutation that inactivates the Dead-end1 (Dnd1) gene. In this perspective, I discuss the possible areas of future investigations to elucidate the mechanism of TGCT development
due to Dnd1 inactivation.
Received 29 September 2006; received after revision 29 January 2007; accepted 19 February 2007 相似文献
16.
Regulation of BMP/Dpp signaling during embryonic development 总被引:9,自引:0,他引:9
17.
Moiseeva EP Leyland ML Bradding P 《Cellular and molecular life sciences : CMLS》2012,69(16):2751-2764
Cell adhesion molecule 1 (CADM1), expressed by human lung mast cells (HLMCs), mediates their adhesion to airway smooth muscle (ASM), and contributes to ASM-dependent HLMC proliferation and survival. CADM1 is expressed in alternatively spliced isoforms, but those present in HLMCs and their function are not known. We cloned three functional and one cryptic non-functional isoform with alternative splicing between exons 7/11 and 1/2, respectively, from HLMCs and human MC lines (HMC-1 and LAD2). Differentiated HLMCs and LAD2 cells expressed the functional isoform SP4 containing exons 7/8/11 (~80% of clones), as well as SP1 (exons 7/8/9/11) and a novel SP6 (exons 7/8/9/10/11). In contrast, immature HMC-1 cells expressed only functional SP4. SP4 overexpression in HMC-1 cells and HLMCs augmented homotypic adhesion to a greater extent than SP1 in various conditions. In contrast, CADM1 downregulation abolished homotypic adhesion, indicating that CADM1 is the sole receptor mediating mast cell aggregation. CADM1-mediated adhesion was enhanced by the presence of cell survival factors. SP1 overexpression in HMC-1 cells compromised survival compared to SP4 overexpression or control. CADM1 downregulation resulted in reduced viability and decreased expression of the pro-survival protein Mcl-1(L), but not Blc-2 or Bcl-X(L), and increased caspase-3/7 activity in both HMC-1 cells and HLMCs. This coincided with decreased basal Kit levels in HLMCs. In summary, human MCs express multiple CADM1 isoforms which exhibit differential regulation of survival and homotypic adhesion. The most highly expressed SP4 isoform is likely to contribute to MC aggregation and longevity in mastocytosis, and augment the pathophysiology of allergic diseases. 相似文献
18.
Yumiko Saga 《Cellular and molecular life sciences : CMLS》2010,67(22):3815-3822
Nanos is known as an evolutionarily conserved RNA-binding protein, the function of which is implicated in germ cell development.
This includes the maintenance of both the primordial germ cells (PGCs) and germline stem cells. In mice, Nanos2 exhibits a
unique feature in which its expression is induced only in the germ cells within the sexually determined male gonad. Nanos2
promotes male germ cell differentiation, while simultaneously suppressing a female program. In addition, Nanos2 is also expressed
in the spermatogonial stem cells and functions as an intrinsic factor to maintain the stem cell population during spermatogenesis.
Detailed cytological and biochemical analyses in embryonic male gonads in the mouse have revealed that Nanos2 localizes to
the P-bodies, a center of RNA processing. It has also been shown that the Nanos2 interacts with protein components of the
deadenylation complex involved in the initial step of the RNA degradation pathway. 相似文献
19.
B. Werner 《Cellular and molecular life sciences : CMLS》1971,27(3):351-353
Summary A new solitary scyphopolyp from submarine caves of the rocky shore near Marseille has been observed to exhibit a new mode of development which is characterized by a reduction of the normally free medusa generation. By the process of strobilation, a chain of sessile hermaphroditic eumedusoids is originated. The germ cells are fertilized and develop into planulae within the gastral room. Self-fertilization has been observed. 相似文献
20.
Ruprecht K Mayer J Sauter M Roemer K Mueller-Lantzsch N 《Cellular and molecular life sciences : CMLS》2008,65(21):3366-3382
The genomes of vertebrates contain sequences that are similar to present-day exogenous retroviruses. Such sequences, called
endogenous retroviruses (ERVs), have resulted from ancestral germ line infections by exogenous retroviruses which have thereafter
been transmitted in a Mendelian fashion. By analogy to exogenous tumorigenic retroviruses, ERVs have been implicated in the
pathogenesis of cancer. Cumulative evidence from animal models indicates that ERVs may participate in the process of malignant
transformation or promote tumor growth, e.g. through insertional mutagenesis or via counteracting tumor immunosurveillance.
Here, we review the role of ERVs in tumorigenesis with focus on human ERVs (HERVs) in human cancer. Although available data
suggest a potential role of HERVs in human cancers, in particular germ cell tumors, the contributions of HERVs to human tumorigenesis
warrant further elucidation. (Part of a Multi-author Review) 相似文献