Tabela com principais espec.
|Species Reactivity||Key Applications||Host||Format||Antibody Type|
|M, R||IHC, WB||Rb||Serum||Polyclonal Antibody|
|Description||Anti-Clara Cell Secretory Protein Antibody|
|Presentation||Rabbit antiserum containing 0.05% sodium azide and 30% glycerol.|
|Application||Detect Clara Cell Secretory Protein using this Anti-Clara Cell Secretory Protein Antibody validated for use in IH & WB.|
|Safety Information according to GHS|
|Material Size||100 µL|
Referências | 22 Disponível | Ver todas as referências
|Visão geral das referências||Aplicação||Espécies||Pub Med ID|
|Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene. |
Wang, Y; Xu, Z; Mao, JH; Hung, MS; Hsieh, D; Au, A; Jablons, DM; You, L
Thoracic cancer 6 480-7 2015
Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied.Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A.Here we show that the use of a recombinant adenovirus expressing Cre-recombinase ("AdenoCre") to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well.Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.
|Alveolar progenitor and stem cells in lung development, renewal and cancer. |
Desai, TJ; Brownfield, DG; Krasnow, MA
Nature 507 190-4 2014
Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.
|In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. |
Maddalo, D; Manchado, E; Concepcion, CP; Bonetti, C; Vidigal, JA; Han, YC; Ogrodowski, P; Crippa, A; Rekhtman, N; de Stanchina, E; Lowe, SW; Ventura, A
Nature 516 423-7 2014
Chromosomal rearrangements have a central role in the pathogenesis of human cancers and often result in the expression of therapeutically actionable gene fusions. A recently discovered example is a fusion between the genes echinoderm microtubule-associated protein like 4 (EML4) and anaplastic lymphoma kinase (ALK), generated by an inversion on the short arm of chromosome 2: inv(2)(p21p23). The EML4-ALK oncogene is detected in a subset of human non-small cell lung cancers (NSCLC) and is clinically relevant because it confers sensitivity to ALK inhibitors. Despite their importance, modelling such genetic events in mice has proven challenging and requires complex manipulation of the germ line. Here we describe an efficient method to induce specific chromosomal rearrangements in vivo using viral-mediated delivery of the CRISPR/Cas9 system to somatic cells of adult animals. We apply it to generate a mouse model of Eml4-Alk-driven lung cancer. The resulting tumours invariably harbour the Eml4-Alk inversion, express the Eml4-Alk fusion gene, display histopathological and molecular features typical of ALK(+) human NSCLCs, and respond to treatment with ALK inhibitors. The general strategy described here substantially expands our ability to model human cancers in mice and potentially in other organisms.
|Rapid modelling of cooperating genetic events in cancer through somatic genome editing. |
Sánchez-Rivera, FJ; Papagiannakopoulos, T; Romero, R; Tammela, T; Bauer, MR; Bhutkar, A; Joshi, NS; Subbaraj, L; Bronson, RT; Xue, W; Jacks, T
Nature 516 428-31 2014
Cancer is a multistep process that involves mutations and other alterations in oncogenes and tumour suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Here we describe a novel CRISPR/Cas9-based approach for rapid functional investigation of candidate genes in well-established autochthonous mouse models of cancer. Using a Kras(G12D)-driven lung cancer model, we performed functional characterization of a panel of tumour suppressor genes with known loss-of-function alterations in human lung cancer. Cre-dependent somatic activation of oncogenic Kras(G12D) combined with CRISPR/Cas9-mediated genome editing of tumour suppressor genes resulted in lung adenocarcinomas with distinct histopathological and molecular features. This rapid somatic genome engineering approach enables functional characterization of putative cancer genes in the lung and other tissues using autochthonous mouse models. We anticipate that this approach can be used to systematically dissect the complex catalogue of mutations identified in cancer genome sequencing studies.
|Profiling molecular changes induced by hydrogen treatment of lung allografts prior to procurement. |
Tanaka, Y; Shigemura, N; Kawamura, T; Noda, K; Isse, K; Stolz, DB; Billiar, TR; Toyoda, Y; Bermudez, CA; Lyons-Weiler, J; Nakao, A
Biochemical and biophysical research communications 425 873-9 2012
We previously demonstrated that donor treatment with inhaled hydrogen protects lung grafts from cold ischemia/reperfusion (I/R) injury during lung transplantation. To elucidate the mechanisms underlying hydrogen's protective effects, we conducted a gene array analysis to identify changes in gene expression associated with hydrogen treatment.Donor rats were exposed to mechanical ventilation with 98% oxygen and 2% nitrogen or 2% hydrogen for 3 h before harvest; lung grafts were stored for 4h in cold Perfadex. Affymetrix gene array analysis of mRNA transcripts was performed on the lung tissue prior to implantation.Pretreatment of donor lungs with hydrogen altered the expression of 229 genes represented on the array (182 upregulated; 47 downregulated). Hydrogen treatment induced several lung surfactant-related genes, ATP synthase genes and stress-response genes. The intracellular surfactant pool, tissue adenosine triphosphate (ATP) levels and heat shock protein 70 (HSP70) expression increased in the hydrogen-treated grafts. Hydrogen treatment also induced the transcription factors C/EBPα and C/EBPβ, which are known regulators of surfactant-related genes.Donor ventilation with hydrogen significantly increases expression of surfactant-related molecules, ATP synthases and stress-response molecules in lung grafts. The induction of these molecules may underlie hydrogen's protective effects against I/R injury during transplantation.
|Proteomic analysis reveals the deregulation of inflammation-related proteins in acupuncture-treated rats with asthma onset. |
Xu, YD; Cui, JM; Wang, Y; Yin, LM; Gao, CK; Liu, XY; Wei, Y; Liu, YY; Jiang, YL; Shan, CX; Yang, YQ
Evidence-based complementary and alternative medicine : eCAM 2012 850512 2012
Although the beneficial effects of acupuncture in asthma treatment have been well documented, little is known regarding the biological basis of this treatment. Changes in the lung proteome of acupuncture-treated rats with asthma onset were comparatively analyzed using a two-dimensional gel electrophoresis (2DE) and mass-spectrometry- (MS-) based proteomic approach. Acupuncture on specific acupuncture points appeared to improve respiratory function and reduce the total number of leukocytes and eosinophils in bronchoalveolar lavage fluid in OVA-induced asthma onset. Image analysis of 2DE gels revealed 32 differentially expressed acupuncture-specific protein spots in asthma onset; 30 of which were successfully identified as 28 unique proteins using LC-MS/MS. Bioinformatic analyses indicated that these altered proteins are most likely involved in inflammation-related biological functions, and the functional associations of these proteins result in an inflammation signaling pathway. Acupuncture regulates the pathway at different levels by regulating several key nodal proteins, including downregulating of proinflammatory proteins (e.g., S100A8, RAGE, and S100A11) and upregulating of anti-inflammatory proteins (e.g., CC10, ANXA5, and sRAGE). These deregulated inflammation-related proteins may mediate, at least in part, the antiasthmatic effect of acupuncture. Further functional investigation of these acupuncture-specific effector proteins could identify new drug candidates for the prophylaxis and treatment of asthma.
|Local fetal lung renin-angiotensin system as a target to treat congenital diaphragmatic hernia. |
Nogueira-Silva, C; Carvalho-Dias, E; Piairo, P; Nunes, S; Baptista, MJ; Moura, RS; Correia-Pinto, J
Molecular medicine (Cambridge, Mass.) 18 231-43 2012
Antenatal stimulation of lung growth is a reasonable approach to treat congenital diaphragmatic hernia (CDH), a disease characterized by pulmonary hypoplasia and hypertension. Several evidences from the literature demonstrated a possible involvement of renin-angiotensin system (RAS) during fetal lung development. Thus, the expression pattern of renin, angiotensin-converting enzyme, angiotensinogen, type 1 (AT₁) and type 2 (AT₂) receptors of angiotensin II (ANGII) was assessed by immunohisto-chemistry throughout gestation, whereas the function of RAS in the fetal lung was evaluated using fetal rat lung explants. These were morphometrically analyzed and intracellular pathway alterations assessed by Western blot. In nitrofen-induced CDH model, pregnant rats were treated with saline or PD-123319. In pups, lung growth, protein/DNA ratio, radial saccular count, epithelial differentiation and lung maturation, vascular morphometry, right ventricular hypertrophy and overload molecular markers, gasometry and survival time were evaluated. Results demonstrated that all RAS components were constitutively expressed in the lung during gestation and that ANGII had a stimulatory effect on lung branching, mediated by AT₁ receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT₂-antagonist (PD-123319) treatment. In vivo antenatal PD-123319 treatment increased lung growth, ameliorated indirect parameters of pulmonary hypertension, improved lung function and survival time in nonventilated CDH pups, without maternal or fetal deleterious effects. Therefore, this study demonstrated a local and physiologically active RAS during lung morphogenesis. Moreover, selective inhibition of AT₂ receptor is presented as a putative antenatal therapy for CDH.
|Loss of Rab27 function results in abnormal lung epithelium structure in mice. |
Bolasco, G; Tracey-White, DC; Tolmachova, T; Thorley, AJ; Tetley, TD; Seabra, MC; Hume, AN
American journal of physiology. Cell physiology 300 C466-76 2011
Rab27 small GTPases regulate secretion and movement of lysosome-related organelles such as T cell cytolytic granules and platelet-dense granules. Previous studies indicated that Rab27a and Rab27b are expressed in the murine lung suggesting that they regulate secretory processes in the lung. Consistent with those studies, we found that Rab27a and Rab27b are expressed in cell types that contain secretory granules: alveolar epithelial type II (AEII) and Clara cells. We then used Rab27a/Rab27b double knockout (DKO) mice to examine the functional consequence of loss of Rab27 proteins in the murine lung. Light and electron microscopy revealed a number of morphological changes in lungs from DKO mice when compared with those in control animals. In aged DKO mice we observed atrophy of the bronchiolar and alveolar epithelium with reduction of cells numbers, thinning of the bronchiolar epithelium and alveolar walls, and enlargement of alveolar airspaces. In these samples we also observed increased numbers of activated foamy alveolar macrophages and granulocyte containing infiltrates together with reduction in the numbers of Clara cells and AEII cells compared with control. At the ultrastructural level we observed accumulation of cytoplasmic membranes and vesicles in Clara cells. Meanwhile, AEII cells in DKO accumulated large mature lamellar bodies and lacked immature/precursor lamellar bodies. We hypothesize that the morphological changes observed at the ultrastructural level in DKO samples result from secretory defects in AEII and Clara cells and that over time these defects lead to atrophy of the epithelium.Texto completo do artigo
|Alveolar epithelial cell therapy with human cord blood-derived hematopoietic progenitor cells. |
De Paepe, ME; Mao, Q; Ghanta, S; Hovanesian, V; Padbury, JF
The American journal of pathology 178 1329-39 2011
The role of umbilical cord blood (CB)-derived stem cell therapy in neonatal lung injury remains undetermined. We investigated the capacity of human CB-derived CD34(+) hematopoietic progenitor cells to regenerate injured alveolar epithelium in newborn mice. Double-transgenic mice with doxycycline (Dox)-dependent lung-specific Fas ligand (FasL) overexpression, treated with Dox between embryonal day 15 and postnatal day 3, served as a model of neonatal lung injury. Single-transgenic non-Dox-responsive littermates were controls. CD34(+) cells (1 × 10(5) to 5 × 10(5)) were administered at postnatal day 5 by intranasal inoculation. Engraftment, respiratory epithelial differentiation, proliferation, and cell fusion were studied at 8 weeks after inoculation. Engrafted cells were readily detected in all recipients and showed a higher incidence of surfactant immunoreactivity and proliferative activity in FasL-overexpressing animals compared with non-FasL-injured littermates. Cord blood-derived cells surrounding surfactant-immunoreactive type II-like cells frequently showed a transitional phenotype between type II and type I cells and/or type I cell-specific podoplanin immunoreactivity. Lack of nuclear colocalization of human and murine genomic material suggested the absence of fusion. In conclusion, human CB-derived CD34(+) cells are capable of long-term pulmonary engraftment, replication, clonal expansion, and reconstitution of injured respiratory epithelium by fusion-independent mechanisms. Cord blood-derived surfactant-positive epithelial cells appear to act as progenitors of the distal respiratory unit, analogous to resident type II cells. Graft proliferation and alveolar epithelial differentiation are promoted by lung injury.
|Lung tissue regeneration after induced injury in Runx3 KO mice. |
Jong-Min Lee,Hyuk-Jae Kwon,Suk-Chul Bae,Han-Sung Jung
Cell and tissue research 341 2010
Runx3 is essential for normal murine lung development, and Runx3 knockout (KO) mice, which die soon after birth, exhibit alveolar hyperplasia. Wound healing, tissue repair, and regeneration mechanisms are necessary in humans for proper early lung development. Previous studies have reported that various signaling molecules, such as pErk, Tgf-beta1, CCSP, pJnk, Smad3, and HSP70 are closely related to wound healing. In order to confirm the relationship between lung defects caused by the loss of function of Runx3 and wound healing, we have localized various wound-healing markers after laser irradiation in wild-type and in Runx3 KO mouse lungs at post-natal day 1. Our results indicate that pERK, Tgf-beta1, CCSP, pJnk, and HSP70 are dramatically down-regulated by loss of Runx3 during lung wound healing. However, Smad3 is up-regulated in the Runx3 KO laser-irradiated lung region. Therefore, the lung wound-healing mechanism is inhibited in the Runx3 KO mouse, which shows abnormal lung architecture, by reduced pErk, Tgf-beta1, CCSP, pJnk, and HSP70 and by induced Smad3.
|Distribution and expression of CD200 in the rat respiratory system under normal and endotoxin-induced pathological conditions. |
Jiang-Shieh YF, Chien HF, Chang CY, Wei TS, Chiu MM, Chen HM, Wu CH
Journal of anatomy 216 2010
Abstract In vivo and in vitro studies have clearly demonstrated that signaling mediated by the interaction of CD200 and its cognate receptor, CD200R, results in an attenuation of inflammatory or autoimmune responses through multiple mechanisms. The present results have shown a differential expression of CD200 in the respiratory tract of intact rats. Along the respiratory passage, CD200 was specifically distributed at the bronchiolar epithelia with intense CD200 immunoreactivity localized at the apical surface of some ciliated epithelial cells; only a limited expression was detected on the Clara cells extending into the alveolar duct. In the alveolar septum, double immunofluorescence showed intense CD200 immunolabeling on the capillary endothelia. A moderate CD200 labeling was observed on the alveolar type II epithelial cells. It was, however, absent in the alveolar type I epithelial cells and the alveolar macrophages. Immunoelectron microscopic study has revealed a specific distribution of CD200 on the luminal front of the thin portion of alveolar endothelia. During endotoxemia, the injured lungs showed a dose- and time-dependent decline of CD200 expression accompanied by a vigorous infiltration of immune cells, some of them expressing ionized calcium binding adapter protein 1 or CD200. Ultrastructural examination further showed that the marked reduction of CD200 expression was mainly attributable to the loss of alveolar endothelial CD200. It is therefore suggested that CD200 expressed by different lung cells may play diverse roles in immune homeostasis of normal lung, in particular, the molecules on alveolar endothelia that may control regular recruitment of immune cells via CD200-CD200R interaction. Additionally, it may contribute to intense infiltration of immune cells following the loss or inefficiency of CD200 under pathological conditions.Texto completo do artigo
|Characterisation of the proximal airway squamous metaplasia induced by chronic tobacco smoke exposure in spontaneously hypertensive rats. |
Bolton, SJ; Pinnion, K; Oreffo, V; Foster, M; Pinkerton, KE
Respiratory research 10 118 2009
Continuous exposure to tobacco smoke (TS) is a key cause of chronic obstructive pulmonary disease (COPD), a complex multifactorial disease that is difficult to model in rodents. The spontaneously hypertensive (SH) rat exhibits several COPD-associated co-morbidities such as hypertension and increased coagulation. We have investigated whether SH rats are a more appropriate animal paradigm of COPD.SH rats were exposed to TS for 6 hours/day, 3 days/week for 14 weeks, and the lung tissues examined by immunohistochemistry.TS induced a CK13-positive squamous metaplasia in proximal airways, which also stained for Ki67 and p63. We hypothesise that this lesion arises by basal cell proliferation, which differentiates to a squamous cell phenotype. Differences in staining profiles for the functional markers CC10 and surfactant D, but not phospho-p38, indicated loss of ability to function appropriately as secretory cells. Within the parenchyma, there were also differences in the staining profiles for CC10 and surfactant D, indicating a possible attempt to compensate for losses in proximal airways. In human COPD sections, areas of CK13-positive squamous metaplasia showed sporadic p63 staining, suggesting that unlike the rat, this is not a basal cell-driven lesion.This study demonstrates that although proximal airway metaplasia in rat and human are both CK13+ and therefore squamous, they potentially arise by different mechanisms.Texto completo do artigo
|Analysis of adeno-associated virus progenitor cell transduction in mouse lung. |
Liu, Xiaoming, et al.
Mol. Ther., 17: 285-93 (2009) 2009
Although recombinant adeno-associated virus (rAAV) has been widely used in lung gene therapy approaches, it remains unclear to what extent commonly used AAV serotypes transduce adult progenitors in the lung. In this study, we evaluated the life span and proliferative capacity of rAAV1-, 2-, and 5-transduced airway cells in mouse lung, using a LacZ-CRE reporter transgenic model and Cre-expressing rAAV. In this model, the expression of CRE recombinase led to permanent genetic marking of transduced cells and their descendants with LacZ. To investigate whether the rAAV-transduced cells included airway progenitors, we injured the airways of rAAV-infected mice with Naphthalene, while simultaneously labeling with 5-bromodeoxyuridine (BrdU) to identify slow-cycling progenitor/stem cells that entered the cell cycle and retained label. Both rAAV5 and rAAV1 vectors were capable of transducing a subset of long-lived Clara cells and alveolar type II (ATII) cells that retained nucleotide label and proliferated following lung injury. Importantly, rAAV1 and 5 appeared to preferentially transduce conducting airway epithelial progenitors that had the capacity to clonally expand, both in culture and in vivo following lung injury. These studies suggest that rAAV may be a useful vector for gene targeting of airway stem/progenitor cells.
|Circadian timing in the lung; a specific role for bronchiolar epithelial cells. |
Gibbs, JE; Beesley, S; Plumb, J; Singh, D; Farrow, S; Ray, DW; Loudon, AS
Endocrinology 150 268-76 2009
In addition to the core circadian oscillator, located within the suprachiasmatic nucleus, numerous peripheral tissues possess self-sustaining circadian timers. In vivo these are entrained and temporally synchronized by signals conveyed from the core oscillator. In the present study, we examine circadian timing in the lung, determine the cellular localization of core clock proteins in both mouse and human lung tissue, and establish the effects of glucocorticoids (widely used in the treatment of asthma) on the pulmonary clock. Using organotypic lung slices prepared from transgenic mPER2::Luc mice, luciferase levels, which report PER2 expression, were measured over a number of days. We demonstrate a robust circadian rhythm in the mouse lung that is responsive to glucocorticoids. Immunohistochemical techniques were used to localize specific expression of core clock proteins, and the glucocorticoid receptor, to the epithelial cells lining the bronchioles in both mouse and human lung. In the mouse, these were established to be Clara cells. Murine Clara cells retained circadian rhythmicity when grown as a pure population in culture. Furthermore, selective ablation of Clara cells resulted in the loss of circadian rhythm in lung slices, demonstrating the importance of this cell type in maintaining overall pulmonary circadian rhythmicity. In summary, we demonstrate that Clara cells are critical for maintaining coherent circadian oscillations in lung tissue. Their coexpression of the glucocorticoid receptor and core clock components establishes them as a likely interface between humoral suprachiasmatic nucleus output and circadian lung physiology.
|Pten inactivation accelerates oncogenic K-ras-initiated tumorigenesis in a mouse model of lung cancer. |
Iwanaga, K; Yang, Y; Raso, MG; Ma, L; Hanna, AE; Thilaganathan, N; Moghaddam, S; Evans, CM; Li, H; Cai, WW; Sato, M; Minna, JD; Wu, H; Creighton, CJ; Demayo, FJ; Wistuba, II; Kurie, JM
Cancer research 68 1119-27 2008
Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non-small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis.
|Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer. |
Yang, Y; Iwanaga, K; Raso, MG; Wislez, M; Hanna, AE; Wieder, ED; Molldrem, JJ; Wistuba, II; Powis, G; Demayo, FJ; Kim, CF; Kurie, JM
PloS one 3 e2220 2008
Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in Western countries. Developing more effective NSCLC therapeutics will require the elucidation of the genetic and biochemical bases for this disease. Bronchioalveolar stem cells (BASCs) are a putative cancer stem cell population in mouse models of oncogenic K-ras-induced lung adenocarcinoma, an histologic subtype of NSCLC. The signals activated by oncogenic K-ras that mediate BASC expansion have not been fully defined.We used genetic and pharmacologic approaches to modulate the activity of phosphatidylinositol 3-kinase (PI3K), a key mediator of oncogenic K-ras, in two genetic mouse models of lung adenocarcinoma. Oncogenic K-ras-induced BASC accumulation and tumor growth were blocked by treatment with a small molecule PI3K inhibitor and enhanced by inactivation of phosphatase and tensin homologue deleted from chromosome 10, a negative regulator of PI3K.We conclude that PI3K is a critical regulator of BASC expansion, supporting treatment strategies to target PI3K in NSCLC patients.
|Targeted cell replacement with bone marrow cells for airway epithelial regeneration. |
Wong, AP; Dutly, AE; Sacher, A; Lee, H; Hwang, DM; Liu, M; Keshavjee, S; Hu, J; Waddell, TK
American journal of physiology. Lung cellular and molecular physiology 293 L740-52 2007
It has been suggested that some adult bone marrow cells (BMC) can localize to the lung and develop tissue-specific characteristics including those of pulmonary epithelial cells. Here, we show that the combination of mild airway injury (naphthalene-induced) as a conditioning regimen to direct the site of BMC localization and transtracheal delivery of short-term cultured BMC enhances airway localization and adoption of an epithelial-like phenotype. Confocal analysis of airway and alveolar-localized BMC (fluorescently labeled) with epithelial markers shows expression of the pulmonary epithelial proteins, Clara cell secretory protein, and surfactant protein C. To confirm epithelial gene expression by BMC, we generated transgenic mice expressing green fluorescent protein (GFP) driven by the epithelial-specific cytokeratin-18 promoter and injected BMC from these mice transtracheally into wild-type recipients after naphthalene-induced airway injury. BMC retention in the lung was observed for at least 120 days following cell delivery with increasing GFP transgene expression over time. Some BMC cultured in vitro over time also expressed GFP transgene, suggesting epithelial transdifferentiation of the BMC. The results indicate that targeted delivery of BMC can promote airway regeneration.
|GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer. |
Anna-Karin M Sjogren, Karin M E Andersson, Meng Liu, Briony A Cutts, Christin Karlsson, Annika M Wahlstrom, Martin Dalin, Carolyn Weinbaum, Patrick J Casey, Andrej Tarkowski, Birgitta Swolin, Stephen G Young, Martin O Bergo
The Journal of clinical investigation 117 1294-304 2007
Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the posttranslational lipidation of CAAX proteins such as RHOA, RAC1, and cell division cycle 42 (CDC42). Inhibition of GGTase-I has been suggested as a strategy to treat cancer and a host of other diseases. Although several GGTase-I inhibitors (GGTIs) have been synthesized, they have very different properties, and the effects of GGTIs and GGTase-I deficiency are unclear. One concern is that inhibiting GGTase-I might lead to severe toxicity. In this study, we determined the effects of GGTase-I deficiency on cell viability and K-RAS-induced cancer development in mice. Inactivating the gene for the critical beta subunit of GGTase-I eliminated GGTase-I activity, disrupted the actin cytoskeleton, reduced cell migration, and blocked the proliferation of fibroblasts expressing oncogenic K-RAS. Moreover, the absence of GGTase-I activity reduced lung tumor formation, eliminated myeloproliferative phenotypes, and increased survival of mice in which expression of oncogenic K-RAS was switched on in lung cells and myeloid cells. Interestingly, several cell types remained viable in the absence of GGTase-I, and myelopoiesis appeared to function normally. These findings suggest that inhibiting GGTase-I may be a useful strategy to treat K-RAS-induced malignancies.Texto completo do artigo
|Clinical aspects of Clara cell 10-kDa protein/ uteroglobin (secretoglobin 1A1) |
Shijubo, Noriharu, et al
Curr Pharm Des, 9:1139-49 (2003) 2003
|Physiological regulation of uteroglobin/CCSP expression. |
Chang, A, et al.
Ann. N. Y. Acad. Sci., 923: 181-92 (2000) 2000
Uteroglobin/CCSP is expressed specifically in the Clara cells. This allows the gene to be used as a marker to identify the elements regulating the physiologic and cell-specific expression of this gene. The regulation of UG/CCSP by IFN-gamma was shown to be at the level of the proximal promoter by the upregulation of HNF3 beta. This has allowed the determination of the factors responsible for the expression of UG/CCSP.
|Clara cell secretory protein decreases lung inflammation after acute virus infection |
Harrod, K S, et al
Am J Physiol, 275:L924-30 (1998) 1998
|Clara cell secretory protein: a determinant of PCB bioaccumulation in mammals |
Stripp, B R, et al
Am J Physiol, 271:L656-64 (1996) 1996