Nuclear accumulation of active Smad complexes is crucial for transduction of transforming growth factor β （TGF-β）- superfamily signals from transmembrane receptors into the nucleus. It is now clear that the nucleo...Nuclear accumulation of active Smad complexes is crucial for transduction of transforming growth factor β （TGF-β）- superfamily signals from transmembrane receptors into the nucleus. It is now clear that the nucleocytoplasmic distributions of Smads, in both the absence and the presence of a TGF-β-superfamily signal, are not static, but instead the Smads are continuously shuttling between the nucleus and the cytoplasm in both conditions. This article presents the evidence for continuous nucleocytoplasmic shuttling of Smads. It then reviews different mechanisms that have been proposed to mediate Smad nuclear import and export, and discusses how the Smad steady-state distributions in the absence and the presence of a TGF-β-superfamily signal are established. Finally, the biological relevance of continuous nucleocytoplasmic shuttling for signaling by TGF-β superfamily members is discussed.展开更多
AIM: To determine the prevalence of antralization at the edge of proximal gastric ulcers, and the effect ofH. pylori eradication on the mucosal appearances.
METHODS: Biopsies were taken from the antrum, body and the u...AIM: To determine the prevalence of antralization at the edge of proximal gastric ulcers, and the effect ofH. pylori eradication on the mucosal appearances.
METHODS: Biopsies were taken from the antrum, body and the ulcer edge of patients with benign proximal gastric ulcers before and one year after treatment. Gastric mucosa was classified as antral, transitional or body type.H. pylori positive patients receivedeither triple therapy, or omeprazole.
RESULTS: Patients with index ulcers in the incisura, body or fundus (n=116) were analyzed. Antral-type mucosa was more prevalent at the ulcer edge inH. pylori-positive patients thanH.pylori-negative patients (93% vs 60%, OR=8.95,95%CI: 2.47-32.4, P=0.001). At one year, there was a significant reduction in the prevalence of antralization (from 93 % to 61%, P=0.004) at the ulcer edge in patients with H. pyloribeing eradicated. However, there was no difference in the prevalence of antralization at the ulcer edge in those with persistent infection.
CONCLUSION: H. pylori infection is associated with antralization at the edge of proximal gastric ulcers, which may be reversible in some patients after eradication of the infection.展开更多
Autophagy is a highly conserved degradative process characterized by the formation of double membrane vesicles called autophagosomes. Autophagy occurs at a basal level in most cells and can be rapidly induced under st...Autophagy is a highly conserved degradative process characterized by the formation of double membrane vesicles called autophagosomes. Autophagy occurs at a basal level in most cells and can be rapidly induced under stress conditions such as amino acid starvation. In multicellular organisms autophagy also plays a role in development, immunity, aging, and tissue homeostasis [ 1 ]. Autophagosomes start out as small membrane structures called phagophores or isolation membranes,展开更多
Antigen interaction with specific IgE bound to the high-affinity Fc receptor for IgE, constitutively expressed on the cell-surface of mast cells, generates signals that cause a shift in the resting state equilibrium o...Antigen interaction with specific IgE bound to the high-affinity Fc receptor for IgE, constitutively expressed on the cell-surface of mast cells, generates signals that cause a shift in the resting state equilibrium of phosphorylation and dephosphorylation events that serves to maintain homeostasis. The outcome of this activated state is the release of a wide array of preformed and newly synthesized pro-inflammatory mediators. During the past few years, the existence of a negative feedback loop initiated upon FcεRI engagement has also been envisaged. This negative signal involves the coordinated action of adaptors, phosphatases and ubiquitin ligases that limits the intensity and duration of positive signals, thus modulating mast cell functions. Relevant to this, others and we have demonstrated that Cbl family proteins control the amplitude of FcεRI-generated signals by specific ubiquitin modification of activated receptor subunits and associated protein tyrosine kinases. In this article, we review advances in our understanding of the molecular mechanisms through which Cbl proteins regulate FcεRI expression and signaling.展开更多
We have investigated the earliest events in commitment of human epidermal keratinocytes to terminal differentiation. Phosphorylated Akt and caspase activation were detected in cells exiting the basal layer of the epid...We have investigated the earliest events in commitment of human epidermal keratinocytes to terminal differentiation. Phosphorylated Akt and caspase activation were detected in cells exiting the basal layer of the epidermis. Activation of Akt by retroviral transduction of primary cultures of human keratinocytes resulted in an increase in abortive clones founded by transit amplifying cells, while inhibition of the upstream kinase, PI3-kinase, inhibited suspension-induced terminal differentiation. Caspase inhibition also blocked differentiation, the primary mediator being caspase 8. Caspase activation was initiated by 2 h in suspension, preceding the onset of expression of the termi- nal differentiation marker involucrin by several hours. Incubation of suspended cells with fibronectin or inhibition of PI3-kinase prevented caspase induction. At 2 h in suspension, keratinocytes that had become committed to terminal differentiation had increased side scatter, were 7-aminoactinomycin D （7-AAD） positive and annexin V negative; they exhibited loss of mitochondrial membrane potential and increased cardiolipin oxidation, but with no increase in reac- tive oxygen species. These properties indicate that the onset of terminal differentiation, while regulated by PI3-kinase and caspases, is not a classical apoptotic process.展开更多
I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of canc...I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of cancer therapy, inherited human genetic disorders and ancient DNA. I initially measured DNA decay, including rates of base loss and cytosine deamination. I have dis- covered several important DNA repair proteins and determined their mechanisms of action. The discovery of uracil-DNA glycosylase defined a new category of repair enzymes with each specialized for different types of DNA damage. The base excision repair pathway was first reconstituted with human proteins in my group. Cell-free analysis for mammalian nucleotide excision repair of DNA was also developed in my laboratory. I found multiple distinct DNA ligases in mammalian cells, and led the first genetic and biochemical work on DNA ligases I, III and IV. I discovered the mam- malian exonucleases DNase III （TREX1） and IV （FEN1）. Interestingly, expression of TREXI was altered in some human autoimmune diseases. I also showed that the mutagenic DNA adduct O6-methylguanine （O6mG） is repaired without removing the guanine from DNA, identifying a sur- prising mechanism by which the methyl group is transferred to a residue in the repair protein itself. A further novel process of DNA repair discovered by my research group is the action of AlkB as an iron-dependent enzyme carrying out oxidative demethylation.展开更多
Rap1A is a small G protein implicated in a spectrum of biological processes such as cell proliferation,adhesion,differentiation,and embryogenesis.The downstream effectors through which Rap1A mediates its diverse effec...Rap1A is a small G protein implicated in a spectrum of biological processes such as cell proliferation,adhesion,differentiation,and embryogenesis.The downstream effectors through which Rap1A mediates its diverse effects are largely unknown.Here we show that Rap1A,but not the related small G proteins Rap2 or Ras,binds the tumor suppressor Ras association domain family 1A(RASSF1A)in a manner that is regulated by phosphorylation of RASSF1A.Interaction with Rap1A is shown to influence the effect of RASSF1A on microtubule behavior.展开更多
It was ever thought that genomic information is transmitted faithfully from generation to generation. But our current knowledge does not indicate that it is the case. For example, genomic variations can be generated f...It was ever thought that genomic information is transmitted faithfully from generation to generation. But our current knowledge does not indicate that it is the case. For example, genomic variations can be generated from DNA replication infidelity and unequal chromosome segregation. Natural decay of DNA molecules is also a fundamental source of changing genomic information. In addition, cellular and organismal exposure to exogenous genotoxic agents such as ultraviolet （UV） light, oxidative stress, chemical mutagens, and radiation can lead to a variety of modifications on DNA constituents, resulting in genome alterations. Fortunately, cells have evolved several response systems to tackle numerous DNA lesions in order to maintain their genome integrity. Among them, check- point control is probably the most well-known one. For exam- ple, checkpoint responds to replication stress, replication fork stalling, double-strand DNA breaks, and various other types of DNA lesions. Increasing experimental evidence indicates that genomic instability is probably the fundamental reason for carcinogenesis. Genomic instability is also found to be a main etiological factor of neurodegenerative diseases, aging, immunodeficiency, etc. Thus, to understand how cells regulate to maintain their genomic stability is of fundamental importance.展开更多
Dear Editor, According to the cancer stem cell （CSC） hypothesis, cancer ceils are organized in a hierarchical manner （Reya et al, 2001）. Indeed, the differentiation state of cancer cells has been linked to their ...Dear Editor, According to the cancer stem cell （CSC） hypothesis, cancer ceils are organized in a hierarchical manner （Reya et al, 2001）. Indeed, the differentiation state of cancer cells has been linked to their proliferative potential, drug response, and ability to metastasize （Clevers, 2011）. Targeting self- renewing, undifferentiated cancer ceils could therefore be of importance for the success of cancer therapies. A classical case of a tumor composed of undifferenti- ated and differentiated cells is the tumor induced by pluripotent stem cells （PSCs） （Ben-David and Benvenisty, 2011）. We have recently identified several small mole- cules termed pluripotent-specific inhibitors （PluriSIns） that selectively target undif- ferentiated tumorigenic PSCs （Ben-David et aL, 2013）. Several of these compounds, including PluriSIn#1, inhibit the activity of stearoyl-coA desaturase （SCD1） （Ben- David et al, 2013）. SCD1 is an endoplasmic reticulum （ER）-membrane protein that plays a key role in the biosynthesis of the mono-unsaturated fatty acid oleate. This novel metabolic vulnerability is in line with the unique metabolome described in PSCs （Panopoulos et al, 2012）.展开更多
文摘Nuclear accumulation of active Smad complexes is crucial for transduction of transforming growth factor β （TGF-β）- superfamily signals from transmembrane receptors into the nucleus. It is now clear that the nucleocytoplasmic distributions of Smads, in both the absence and the presence of a TGF-β-superfamily signal, are not static, but instead the Smads are continuously shuttling between the nucleus and the cytoplasm in both conditions. This article presents the evidence for continuous nucleocytoplasmic shuttling of Smads. It then reviews different mechanisms that have been proposed to mediate Smad nuclear import and export, and discusses how the Smad steady-state distributions in the absence and the presence of a TGF-β-superfamily signal are established. Finally, the biological relevance of continuous nucleocytoplasmic shuttling for signaling by TGF-β superfamily members is discussed.
基金the Seed Funding for Basic Research 2001(301/01),The University of Hong Konga competitive earmarked research grant from the Research Grants Council of Hong Kong Special Administrative Region,China(HKU7318/01M)to HH-X Xia
文摘AIM: To determine the prevalence of antralization at the edge of proximal gastric ulcers, and the effect ofH. pylori eradication on the mucosal appearances.
METHODS: Biopsies were taken from the antrum, body and the ulcer edge of patients with benign proximal gastric ulcers before and one year after treatment. Gastric mucosa was classified as antral, transitional or body type.H. pylori positive patients receivedeither triple therapy, or omeprazole.
RESULTS: Patients with index ulcers in the incisura, body or fundus (n=116) were analyzed. Antral-type mucosa was more prevalent at the ulcer edge inH. pylori-positive patients thanH.pylori-negative patients (93% vs 60%, OR=8.95,95%CI: 2.47-32.4, P=0.001). At one year, there was a significant reduction in the prevalence of antralization (from 93 % to 61%, P=0.004) at the ulcer edge in patients with H. pyloribeing eradicated. However, there was no difference in the prevalence of antralization at the ulcer edge in those with persistent infection.
CONCLUSION: H. pylori infection is associated with antralization at the edge of proximal gastric ulcers, which may be reversible in some patients after eradication of the infection.
文摘Autophagy is a highly conserved degradative process characterized by the formation of double membrane vesicles called autophagosomes. Autophagy occurs at a basal level in most cells and can be rapidly induced under stress conditions such as amino acid starvation. In multicellular organisms autophagy also plays a role in development, immunity, aging, and tissue homeostasis [ 1 ]. Autophagosomes start out as small membrane structures called phagophores or isolation membranes,
文摘Antigen interaction with specific IgE bound to the high-affinity Fc receptor for IgE, constitutively expressed on the cell-surface of mast cells, generates signals that cause a shift in the resting state equilibrium of phosphorylation and dephosphorylation events that serves to maintain homeostasis. The outcome of this activated state is the release of a wide array of preformed and newly synthesized pro-inflammatory mediators. During the past few years, the existence of a negative feedback loop initiated upon FcεRI engagement has also been envisaged. This negative signal involves the coordinated action of adaptors, phosphatases and ubiquitin ligases that limits the intensity and duration of positive signals, thus modulating mast cell functions. Relevant to this, others and we have demonstrated that Cbl family proteins control the amplitude of FcεRI-generated signals by specific ubiquitin modification of activated receptor subunits and associated protein tyrosine kinases. In this article, we review advances in our understanding of the molecular mechanisms through which Cbl proteins regulate FcεRI expression and signaling.
文摘We have investigated the earliest events in commitment of human epidermal keratinocytes to terminal differentiation. Phosphorylated Akt and caspase activation were detected in cells exiting the basal layer of the epidermis. Activation of Akt by retroviral transduction of primary cultures of human keratinocytes resulted in an increase in abortive clones founded by transit amplifying cells, while inhibition of the upstream kinase, PI3-kinase, inhibited suspension-induced terminal differentiation. Caspase inhibition also blocked differentiation, the primary mediator being caspase 8. Caspase activation was initiated by 2 h in suspension, preceding the onset of expression of the termi- nal differentiation marker involucrin by several hours. Incubation of suspended cells with fibronectin or inhibition of PI3-kinase prevented caspase induction. At 2 h in suspension, keratinocytes that had become committed to terminal differentiation had increased side scatter, were 7-aminoactinomycin D （7-AAD） positive and annexin V negative; they exhibited loss of mitochondrial membrane potential and increased cardiolipin oxidation, but with no increase in reac- tive oxygen species. These properties indicate that the onset of terminal differentiation, while regulated by PI3-kinase and caspases, is not a classical apoptotic process.
文摘I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of cancer therapy, inherited human genetic disorders and ancient DNA. I initially measured DNA decay, including rates of base loss and cytosine deamination. I have dis- covered several important DNA repair proteins and determined their mechanisms of action. The discovery of uracil-DNA glycosylase defined a new category of repair enzymes with each specialized for different types of DNA damage. The base excision repair pathway was first reconstituted with human proteins in my group. Cell-free analysis for mammalian nucleotide excision repair of DNA was also developed in my laboratory. I found multiple distinct DNA ligases in mammalian cells, and led the first genetic and biochemical work on DNA ligases I, III and IV. I discovered the mam- malian exonucleases DNase III （TREX1） and IV （FEN1）. Interestingly, expression of TREXI was altered in some human autoimmune diseases. I also showed that the mutagenic DNA adduct O6-methylguanine （O6mG） is repaired without removing the guanine from DNA, identifying a sur- prising mechanism by which the methyl group is transferred to a residue in the repair protein itself. A further novel process of DNA repair discovered by my research group is the action of AlkB as an iron-dependent enzyme carrying out oxidative demethylation.
基金SKV also acknowledges the award of the Commonwealth Scholarship and the financial support received from the Department of Medical Oncology,Medical Sciences Division,The University of Oxford,Oxford,UK and the Cancer Research UK.
文摘Rap1A is a small G protein implicated in a spectrum of biological processes such as cell proliferation,adhesion,differentiation,and embryogenesis.The downstream effectors through which Rap1A mediates its diverse effects are largely unknown.Here we show that Rap1A,but not the related small G proteins Rap2 or Ras,binds the tumor suppressor Ras association domain family 1A(RASSF1A)in a manner that is regulated by phosphorylation of RASSF1A.Interaction with Rap1A is shown to influence the effect of RASSF1A on microtubule behavior.
文摘It was ever thought that genomic information is transmitted faithfully from generation to generation. But our current knowledge does not indicate that it is the case. For example, genomic variations can be generated from DNA replication infidelity and unequal chromosome segregation. Natural decay of DNA molecules is also a fundamental source of changing genomic information. In addition, cellular and organismal exposure to exogenous genotoxic agents such as ultraviolet （UV） light, oxidative stress, chemical mutagens, and radiation can lead to a variety of modifications on DNA constituents, resulting in genome alterations. Fortunately, cells have evolved several response systems to tackle numerous DNA lesions in order to maintain their genome integrity. Among them, check- point control is probably the most well-known one. For exam- ple, checkpoint responds to replication stress, replication fork stalling, double-strand DNA breaks, and various other types of DNA lesions. Increasing experimental evidence indicates that genomic instability is probably the fundamental reason for carcinogenesis. Genomic instability is also found to be a main etiological factor of neurodegenerative diseases, aging, immunodeficiency, etc. Thus, to understand how cells regulate to maintain their genomic stability is of fundamental importance.
文摘Dear Editor, According to the cancer stem cell （CSC） hypothesis, cancer ceils are organized in a hierarchical manner （Reya et al, 2001）. Indeed, the differentiation state of cancer cells has been linked to their proliferative potential, drug response, and ability to metastasize （Clevers, 2011）. Targeting self- renewing, undifferentiated cancer ceils could therefore be of importance for the success of cancer therapies. A classical case of a tumor composed of undifferenti- ated and differentiated cells is the tumor induced by pluripotent stem cells （PSCs） （Ben-David and Benvenisty, 2011）. We have recently identified several small mole- cules termed pluripotent-specific inhibitors （PluriSIns） that selectively target undif- ferentiated tumorigenic PSCs （Ben-David et aL, 2013）. Several of these compounds, including PluriSIn#1, inhibit the activity of stearoyl-coA desaturase （SCD1） （Ben- David et al, 2013）. SCD1 is an endoplasmic reticulum （ER）-membrane protein that plays a key role in the biosynthesis of the mono-unsaturated fatty acid oleate. This novel metabolic vulnerability is in line with the unique metabolome described in PSCs （Panopoulos et al, 2012）.
