Vanessa Craig - Academia.edu (original) (raw)
Papers by Vanessa Craig
D29. STICKY SITUATION: MULTI-FATE OF CELL AND MATRIX INTERACTIONS, 2012
A101. INFLAMMATION AND REPAIR IN LUNG INJURY, 2010
Page 1. / Poster Discussion Session / Sunday, May 16/1:30 PM-4:00 PM / Room A101 INFLAMMATION AND... more Page 1. / Poster Discussion Session / Sunday, May 16/1:30 PM-4:00 PM / Room A101 INFLAMMATION AND REPAIR IN LUNG INJURY 353-355 (Third Level), Morial Convention Center Matrix Metalloproteinase-8 (MMP-8) Has ...
D36. ANIMAL MODELS OF PULMONARY FIBROSIS, 2011
Page 1. / Thematic Poster Session / Wednesday, May 18/8:15 AM-4:30 PM / Area L, D36 ANIMAL MODELS... more Page 1. / Thematic Poster Session / Wednesday, May 18/8:15 AM-4:30 PM / Area L, D36 ANIMAL MODELS OF PULMONARY FIBROSIS Hall B (Upper Level), Colorado Convention Center Matrix Metalloproteinase-8 (mmp-8 ...
Biochemical Society Transactions, Dec 1, 2008
Nephrol Dialysis Transplant, Sep 9, 2010
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background o... more Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background of chronic inflammation caused by persistent Helicobacter pylori infection. The clinical and histopathological features of the human tumor can be reproduced by Helicobacter infection of BALB/c mice. In this study, we have analyzed the antibody sequences and antigen specificity of a panel of murine and human MALT lymphomaderived antibodies. We find that a majority of tumors in patients as well as experimentally infected mice are monoclonal. The tumor immunoglobulin heavy chain genes have undergone somatic hypermutation, and approximately half of all tumors show evidence of intraclonal variation and positive and/or negative selective pressure. Recombinantly expressed MALT lymphoma antibodies bind with intermediate affinity to various unrelated self and foreign antigens, including Helicobacter sonicate, IgG, DNA and stomach extract; antigen binding is blocked in a dose-dependent manner in competitive ELISAs. A strong bias towards the use of V H gene segments previously linked to auto-and/or polyreactive antibodies in B-cell malignancies or autoimmune pathologies supports the experimental finding of polyreactivity. Our results suggest that MALT lymphoma development may be facilitated by an array of local self and foreign antigens providing direct antigenic stimulation of the tumor cells via their B-cell receptor.
American journal of respiratory cell and molecular biology, Jan 29, 2015
Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high mo... more Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in IPF patients and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous non-matrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis have demonstrated that most MMPs promote (rather than inhibit) the development of pulmonary fibrosis and have identified diverse mechanisms involved. These mechanisms include MMPs: 1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7);...
Mammal Research, 2014
Forest habitats after harvesting or wildfire disturbance are usually dominated by early successio... more Forest habitats after harvesting or wildfire disturbance are usually dominated by early successional vegetation for up to 5-10 years, as well as downed wood or coarse woody debris (CWD). Abundance of Microtus voles is often highest in these sites with sufficient plant cover being crucial for population increases. The role of CWD for voles is less clear. We tested the hypotheses (H) that (H 1) abundance and reproduction of meadow vole (Microtus pennsylvanicus) and longtailed vole (Microtus longicaudus) populations would be higher on sites with greater amounts of downed wood and that (H 2) this relationship would be stronger on sites with sparse vegetation cover. There were two study areas: a dry Douglas-fir (Pseudotsuga menziesii)-lodgepole pine (Pinus contorta) forest and a high-elevation Engelmann spruce (Picea engelmannii)-subalpine fir (Abies lasiocarpa) forest in southern British Columbia, Canada. We monitored the responses of meadow voles and long-tailed voles to three levels of downed wood over a 4-year period in replicated clear-cut sites at each area. Amount of downed wood did not positively influence meadow or long-tailed vole population dynamics, and hence, H 1 was not supported. Variability in meadow vole numbers and vegetation precluded a test of H 2 for this microtine. In dry forests, abundance of meadow voles on clear-cuts was related to the availability of cover and vertical structure provided by herbs and grasses. Vegetation cover was sparse in the high-elevation clear-cuts and longtailed voles did seem to be positively affected by the number of pieces of CWD, but not by volume, and hence H 2 appeared to be partly supported. In high-elevation or otherwise slowgrowing areas, and in areas with long-tailed voles, downed wood left after harvest may provide some cover and structure.
The Vancouver Island water shrew (Sorex palustris brooksi)1 is a rare subspecies found only on Va... more The Vancouver Island water shrew (Sorex palustris brooksi)1 is a rare subspecies found only on Vancouver Island, British Columbia. It is a riparian specialist, specially adapted to a semi-aquatic lifestyle and strongly associated with the land/water interface. Human-related activities on Vancouver Island have resulted in the loss or degradation of habitat for S. p. brooksi. Mitigation efforts aimed at stream
Cancer discovery, 2012
The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug r... more The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.
PLoS ONE, 2014
Objectives: Matrix metalloproteinase-8 (MMP-8) promotes lung fibrotic responses to bleomycin in m... more Objectives: Matrix metalloproteinase-8 (MMP-8) promotes lung fibrotic responses to bleomycin in mice. Although prior studies reported that MMP-8 levels are increased in plasma and bronchoalveolar lavage fluid (BALF) samples from IPF patients, neither the bioactive forms nor the cellular sources of MMP-8 in idiopathic pulmonary fibrosis (IPF) patients have been identified. It is not known whether MMP-8 expression is dys-regulated in IPF leukocytes or whether MMP-8 plasma levels correlate with IPF outcomes. Our goal was to address these knowledge gaps.
Leukemia, 2010
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of ch... more Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of chronic inflammation caused by Helicobacter pylori infection. Most pathophysiological features of the early stages of MALT lymphomagenesis can be reproduced by experimental infection of BALB/c mice with Helicobacter species. We have previously shown that MALT lymphomas are infiltrated by T-helper cell type 2-polarized T cells and that human and murine tumor B cells carry polyreactive surface immunoglobulins. Using the murine model of the disease, in this study we show that explanted tumor B cells proliferate upon stimulation with the same panel of self and foreign antigens that are recognized by their surface antibodies. Tumor cell proliferation is strongly enhanced by the presence of intratumoral CD4 þ T cells in a CD40/CD40L-independent manner. A large proportion of tumor-infiltrating CD4 þ T cells are CD25 þ FoxP3 þ regulatory T cells (Tregs) with highly suppressive activity, which are recruited by the tumor cells through secretion of the Treg-attracting chemokines CCL17 and CCL22. The depletion of CD25 þ cells was as efficient as CD4 þ T cell depletion in blocking tumor growth in vitro and in vivo. In conclusion, our data suggest that B-cell receptor-derived signals cooperate with T-helper cell signals in driving the progression of MALT lymphoma, providing an explanation for the unique antigen dependence of this B-cell malignancy.
The Journal of Immunology, 2013
Matrix metalloproteinase-8 (MMP-8) is a potent interstitial collagenase thought to be expressed m... more Matrix metalloproteinase-8 (MMP-8) is a potent interstitial collagenase thought to be expressed mainly by polymorphonuclear neutrophils. To determine whether MMP-8 regulates lung inflammatory or fibrotic responses to bleomycin, we delivered bleomycin by the intratracheal route to wild-type (WT) versus Mmp-8−/− mice and quantified MMP-8 expression, and inflammation and fibrosis in the lung samples. Mmp-8 steady state mRNA and protein levels increase in whole lung and bronchoalveolar lavage samples when WT mice are treated with bleomycin. Activated murine lung fibroblasts express Mmp-8 in vitro. MMP-8 expression is increased in leukocytes in the lungs of patients with idiopathic pulmonary fibrosis compared with control lung samples. Compared with bleomycin-treated WT mice, bleomycin-treated Mmp-8−/− mice have greater lung inflammation, but reduced lung fibrosis. Whereas bleomycin-treated Mmp-8−/− and WT mice have similar lung levels of several pro- and antifibrotic mediators (TGF-β, I...
The Journal of Immunology, 2013
To determine whether a disintegrin and metalloproteinase-8 (Adam8) regulates allergic airway infl... more To determine whether a disintegrin and metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyperresponsiveness (AHR), we compared AAI and AHR in wild-type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with OVA or house dust mite protein extract. OVA- and house dust mite–treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some Th2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT m...
Journal of Biological Chemistry, 2013
Background: A putative intramolecular interaction in the Islet 1 (Isl1) transcription factor inhi... more Background: A putative intramolecular interaction in the Islet 1 (Isl1) transcription factor inhibits DNA binding. Results: An intramolecular interaction between the LIM domains and LIM homeobox 3 (Lhx3)-binding domain in Isl1 was characterized. Conclusion: The intramolecular interaction within Isl1 is weak but specific. Significance: This interaction likely prevents unproductive binding in the absence of cofactor proteins. Islet 1 (Isl1) is a transcription factor of the LIM-homeodomain (LIM-HD) protein family and is essential for many developmental processes. LIM-HD proteins all contain two proteininteracting LIM domains, a DNA-binding homeodomain (HD), and a C-terminal region. In Isl1, the C-terminal region also contains the LIM homeobox 3 (Lhx3)-binding domain (LBD), which interacts with the LIM domains of Lhx3. The LIM domains of Isl1 have been implicated in inhibition of DNA binding potentially through an intramolecular interaction with or close to the HD. Here we investigate the LBD as a candidate intramolecular interaction domain. Competitive yeast-two hybrid experiments indicate that the LIM domains and LBD from Isl1 can interact with apparently low affinity, consistent with no detection of an intermolecular interaction in the same system. Nuclear magnetic resonance studies show that the interaction is specific, whereas substitution of the LBD with peptides of the same amino acid composition but different sequence is not specific. We solved the crystal structure of a similar but higher affinity complex between the LIM domains of Isl1 and the LIM interaction domain from the LIM-HD cofactor protein LIM domainbinding protein 1 (Ldb1) and used these coordinates to generate a homology model of the intramolecular interaction that indicates poorer complementarity for the weak intramolecular interaction. The intramolecular interaction in Isl1 may provide protection against aggregation, minimize unproductive DNA binding, and facilitate cofactor exchange within the cell.
Current Pharmaceutical Design, 2012
microRNAs (miRNAs) comprise a recently discovered class of non-coding RNAs with regulatory functi... more microRNAs (miRNAs) comprise a recently discovered class of non-coding RNAs with regulatory functions in post-transcriptional gene expression control. Many miRNAs are located in genomic regions that are frequently deleted in cancer, or are subject to epigenetic and transcriptional deregulation in cancer cells. The miRNA transcriptome of cancer cells is very different from that of their normal cell counterparts. miRNAs can exhibit oncogenic or tumor suppressive or even both properties depending on the specific targets and cellular context. It is becoming increasingly clear that miRNAs not only serve as useful tumor biomarkers with implications for diagnosis, prognosis and the prediction of treatment responses, but may also be used for targeted cancer treatment and even as therapeutics. In this review, we provide an overview of recent advances in our understanding of the tumor suppressor miRNAs and oncomiRs involved in the pathogenesis of leukemias and lymphomas, and their target transcripts in cancer signaling networks. In particular, we focus on the role of miRNAs in chronic lymphocytic and acute lymphoblastic leukemia and in B-cell lymphomas. In the second part, we review the various alternative strategies of targeting miRNAs in cancer therapy. Methods of oncomiR antagonization by antagomiRs or locked nucleid acids are contrasted with strategies that harness the tumor suppressive properties of certain miRNAs for cancer treatment. Preclinical progress, also with regard to delivery strategies, possible side effects and other pharmacological aspects, is presented along with results from the first human trials assessing the safety and efficacy of miRNA-targeting therapeutics.
D29. STICKY SITUATION: MULTI-FATE OF CELL AND MATRIX INTERACTIONS, 2012
A101. INFLAMMATION AND REPAIR IN LUNG INJURY, 2010
Page 1. / Poster Discussion Session / Sunday, May 16/1:30 PM-4:00 PM / Room A101 INFLAMMATION AND... more Page 1. / Poster Discussion Session / Sunday, May 16/1:30 PM-4:00 PM / Room A101 INFLAMMATION AND REPAIR IN LUNG INJURY 353-355 (Third Level), Morial Convention Center Matrix Metalloproteinase-8 (MMP-8) Has ...
D36. ANIMAL MODELS OF PULMONARY FIBROSIS, 2011
Page 1. / Thematic Poster Session / Wednesday, May 18/8:15 AM-4:30 PM / Area L, D36 ANIMAL MODELS... more Page 1. / Thematic Poster Session / Wednesday, May 18/8:15 AM-4:30 PM / Area L, D36 ANIMAL MODELS OF PULMONARY FIBROSIS Hall B (Upper Level), Colorado Convention Center Matrix Metalloproteinase-8 (mmp-8 ...
Biochemical Society Transactions, Dec 1, 2008
Nephrol Dialysis Transplant, Sep 9, 2010
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background o... more Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background of chronic inflammation caused by persistent Helicobacter pylori infection. The clinical and histopathological features of the human tumor can be reproduced by Helicobacter infection of BALB/c mice. In this study, we have analyzed the antibody sequences and antigen specificity of a panel of murine and human MALT lymphomaderived antibodies. We find that a majority of tumors in patients as well as experimentally infected mice are monoclonal. The tumor immunoglobulin heavy chain genes have undergone somatic hypermutation, and approximately half of all tumors show evidence of intraclonal variation and positive and/or negative selective pressure. Recombinantly expressed MALT lymphoma antibodies bind with intermediate affinity to various unrelated self and foreign antigens, including Helicobacter sonicate, IgG, DNA and stomach extract; antigen binding is blocked in a dose-dependent manner in competitive ELISAs. A strong bias towards the use of V H gene segments previously linked to auto-and/or polyreactive antibodies in B-cell malignancies or autoimmune pathologies supports the experimental finding of polyreactivity. Our results suggest that MALT lymphoma development may be facilitated by an array of local self and foreign antigens providing direct antigenic stimulation of the tumor cells via their B-cell receptor.
American journal of respiratory cell and molecular biology, Jan 29, 2015
Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high mo... more Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in IPF patients and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous non-matrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis have demonstrated that most MMPs promote (rather than inhibit) the development of pulmonary fibrosis and have identified diverse mechanisms involved. These mechanisms include MMPs: 1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7);...
Mammal Research, 2014
Forest habitats after harvesting or wildfire disturbance are usually dominated by early successio... more Forest habitats after harvesting or wildfire disturbance are usually dominated by early successional vegetation for up to 5-10 years, as well as downed wood or coarse woody debris (CWD). Abundance of Microtus voles is often highest in these sites with sufficient plant cover being crucial for population increases. The role of CWD for voles is less clear. We tested the hypotheses (H) that (H 1) abundance and reproduction of meadow vole (Microtus pennsylvanicus) and longtailed vole (Microtus longicaudus) populations would be higher on sites with greater amounts of downed wood and that (H 2) this relationship would be stronger on sites with sparse vegetation cover. There were two study areas: a dry Douglas-fir (Pseudotsuga menziesii)-lodgepole pine (Pinus contorta) forest and a high-elevation Engelmann spruce (Picea engelmannii)-subalpine fir (Abies lasiocarpa) forest in southern British Columbia, Canada. We monitored the responses of meadow voles and long-tailed voles to three levels of downed wood over a 4-year period in replicated clear-cut sites at each area. Amount of downed wood did not positively influence meadow or long-tailed vole population dynamics, and hence, H 1 was not supported. Variability in meadow vole numbers and vegetation precluded a test of H 2 for this microtine. In dry forests, abundance of meadow voles on clear-cuts was related to the availability of cover and vertical structure provided by herbs and grasses. Vegetation cover was sparse in the high-elevation clear-cuts and longtailed voles did seem to be positively affected by the number of pieces of CWD, but not by volume, and hence H 2 appeared to be partly supported. In high-elevation or otherwise slowgrowing areas, and in areas with long-tailed voles, downed wood left after harvest may provide some cover and structure.
The Vancouver Island water shrew (Sorex palustris brooksi)1 is a rare subspecies found only on Va... more The Vancouver Island water shrew (Sorex palustris brooksi)1 is a rare subspecies found only on Vancouver Island, British Columbia. It is a riparian specialist, specially adapted to a semi-aquatic lifestyle and strongly associated with the land/water interface. Human-related activities on Vancouver Island have resulted in the loss or degradation of habitat for S. p. brooksi. Mitigation efforts aimed at stream
Cancer discovery, 2012
The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug r... more The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.
PLoS ONE, 2014
Objectives: Matrix metalloproteinase-8 (MMP-8) promotes lung fibrotic responses to bleomycin in m... more Objectives: Matrix metalloproteinase-8 (MMP-8) promotes lung fibrotic responses to bleomycin in mice. Although prior studies reported that MMP-8 levels are increased in plasma and bronchoalveolar lavage fluid (BALF) samples from IPF patients, neither the bioactive forms nor the cellular sources of MMP-8 in idiopathic pulmonary fibrosis (IPF) patients have been identified. It is not known whether MMP-8 expression is dys-regulated in IPF leukocytes or whether MMP-8 plasma levels correlate with IPF outcomes. Our goal was to address these knowledge gaps.
Leukemia, 2010
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of ch... more Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of chronic inflammation caused by Helicobacter pylori infection. Most pathophysiological features of the early stages of MALT lymphomagenesis can be reproduced by experimental infection of BALB/c mice with Helicobacter species. We have previously shown that MALT lymphomas are infiltrated by T-helper cell type 2-polarized T cells and that human and murine tumor B cells carry polyreactive surface immunoglobulins. Using the murine model of the disease, in this study we show that explanted tumor B cells proliferate upon stimulation with the same panel of self and foreign antigens that are recognized by their surface antibodies. Tumor cell proliferation is strongly enhanced by the presence of intratumoral CD4 þ T cells in a CD40/CD40L-independent manner. A large proportion of tumor-infiltrating CD4 þ T cells are CD25 þ FoxP3 þ regulatory T cells (Tregs) with highly suppressive activity, which are recruited by the tumor cells through secretion of the Treg-attracting chemokines CCL17 and CCL22. The depletion of CD25 þ cells was as efficient as CD4 þ T cell depletion in blocking tumor growth in vitro and in vivo. In conclusion, our data suggest that B-cell receptor-derived signals cooperate with T-helper cell signals in driving the progression of MALT lymphoma, providing an explanation for the unique antigen dependence of this B-cell malignancy.
The Journal of Immunology, 2013
Matrix metalloproteinase-8 (MMP-8) is a potent interstitial collagenase thought to be expressed m... more Matrix metalloproteinase-8 (MMP-8) is a potent interstitial collagenase thought to be expressed mainly by polymorphonuclear neutrophils. To determine whether MMP-8 regulates lung inflammatory or fibrotic responses to bleomycin, we delivered bleomycin by the intratracheal route to wild-type (WT) versus Mmp-8−/− mice and quantified MMP-8 expression, and inflammation and fibrosis in the lung samples. Mmp-8 steady state mRNA and protein levels increase in whole lung and bronchoalveolar lavage samples when WT mice are treated with bleomycin. Activated murine lung fibroblasts express Mmp-8 in vitro. MMP-8 expression is increased in leukocytes in the lungs of patients with idiopathic pulmonary fibrosis compared with control lung samples. Compared with bleomycin-treated WT mice, bleomycin-treated Mmp-8−/− mice have greater lung inflammation, but reduced lung fibrosis. Whereas bleomycin-treated Mmp-8−/− and WT mice have similar lung levels of several pro- and antifibrotic mediators (TGF-β, I...
The Journal of Immunology, 2013
To determine whether a disintegrin and metalloproteinase-8 (Adam8) regulates allergic airway infl... more To determine whether a disintegrin and metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyperresponsiveness (AHR), we compared AAI and AHR in wild-type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with OVA or house dust mite protein extract. OVA- and house dust mite–treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some Th2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT m...
Journal of Biological Chemistry, 2013
Background: A putative intramolecular interaction in the Islet 1 (Isl1) transcription factor inhi... more Background: A putative intramolecular interaction in the Islet 1 (Isl1) transcription factor inhibits DNA binding. Results: An intramolecular interaction between the LIM domains and LIM homeobox 3 (Lhx3)-binding domain in Isl1 was characterized. Conclusion: The intramolecular interaction within Isl1 is weak but specific. Significance: This interaction likely prevents unproductive binding in the absence of cofactor proteins. Islet 1 (Isl1) is a transcription factor of the LIM-homeodomain (LIM-HD) protein family and is essential for many developmental processes. LIM-HD proteins all contain two proteininteracting LIM domains, a DNA-binding homeodomain (HD), and a C-terminal region. In Isl1, the C-terminal region also contains the LIM homeobox 3 (Lhx3)-binding domain (LBD), which interacts with the LIM domains of Lhx3. The LIM domains of Isl1 have been implicated in inhibition of DNA binding potentially through an intramolecular interaction with or close to the HD. Here we investigate the LBD as a candidate intramolecular interaction domain. Competitive yeast-two hybrid experiments indicate that the LIM domains and LBD from Isl1 can interact with apparently low affinity, consistent with no detection of an intermolecular interaction in the same system. Nuclear magnetic resonance studies show that the interaction is specific, whereas substitution of the LBD with peptides of the same amino acid composition but different sequence is not specific. We solved the crystal structure of a similar but higher affinity complex between the LIM domains of Isl1 and the LIM interaction domain from the LIM-HD cofactor protein LIM domainbinding protein 1 (Ldb1) and used these coordinates to generate a homology model of the intramolecular interaction that indicates poorer complementarity for the weak intramolecular interaction. The intramolecular interaction in Isl1 may provide protection against aggregation, minimize unproductive DNA binding, and facilitate cofactor exchange within the cell.
Current Pharmaceutical Design, 2012
microRNAs (miRNAs) comprise a recently discovered class of non-coding RNAs with regulatory functi... more microRNAs (miRNAs) comprise a recently discovered class of non-coding RNAs with regulatory functions in post-transcriptional gene expression control. Many miRNAs are located in genomic regions that are frequently deleted in cancer, or are subject to epigenetic and transcriptional deregulation in cancer cells. The miRNA transcriptome of cancer cells is very different from that of their normal cell counterparts. miRNAs can exhibit oncogenic or tumor suppressive or even both properties depending on the specific targets and cellular context. It is becoming increasingly clear that miRNAs not only serve as useful tumor biomarkers with implications for diagnosis, prognosis and the prediction of treatment responses, but may also be used for targeted cancer treatment and even as therapeutics. In this review, we provide an overview of recent advances in our understanding of the tumor suppressor miRNAs and oncomiRs involved in the pathogenesis of leukemias and lymphomas, and their target transcripts in cancer signaling networks. In particular, we focus on the role of miRNAs in chronic lymphocytic and acute lymphoblastic leukemia and in B-cell lymphomas. In the second part, we review the various alternative strategies of targeting miRNAs in cancer therapy. Methods of oncomiR antagonization by antagomiRs or locked nucleid acids are contrasted with strategies that harness the tumor suppressive properties of certain miRNAs for cancer treatment. Preclinical progress, also with regard to delivery strategies, possible side effects and other pharmacological aspects, is presented along with results from the first human trials assessing the safety and efficacy of miRNA-targeting therapeutics.