more information
Search within Results:

Select All    Deselect All
 |   | 
Details
   print
  Records Links
Author (up) Kim, A.D.; Melick, C.H.; Clements, W.K.; Stachura, D.L.; Distel, M.; Panakova, D.; MacRae, C.; Mork, L.A.; Crump, J.G.; Traver, D. file  url
doi  openurl
  Title Discrete Notch signaling requirements in the specification of hematopoietic stem cells Type Journal Article
  Year 2014 Publication The EMBO Journal Abbreviated Journal Embo J  
  Volume 33 Issue 20 Pages 2363-2373  
  Keywords Animals; Cell Differentiation; *Gene Expression Regulation, Developmental; Hemangioblasts/cytology/physiology; Hematopoietic Stem Cells/cytology/*physiology; Homeodomain Proteins/genetics/*metabolism; Nerve Tissue Proteins/genetics/*metabolism; Receptor, Notch1/genetics/*metabolism; Receptors, Notch/genetics/*metabolism; Signal Transduction; Somites/cytology/embryology/physiology; Wnt Proteins/genetics/metabolism; Zebrafish/embryology/genetics/*physiology; Zebrafish Proteins/genetics/*metabolism; Notch; hematopoietic stem cell; hemogenic endothelium; somite  
  Abstract Hematopoietic stem cells (HSCs) require multiple molecular inputs for proper specification, including activity of the Notch signaling pathway. A requirement for the Notch1 and dispensability of the Notch2 receptor has been demonstrated in mice, but the role of the remaining Notch receptors has not been investigated. Here, we demonstrate that three of the four Notch receptors are independently required for the specification of HSCs in the zebrafish. The orthologues of the murine Notch1 receptor, Notch1a and Notch1b, are each required intrinsically to fate HSCs, just prior to their emergence from aortic hemogenic endothelium. By contrast, the Notch3 receptor is required earlier within the developing somite to regulate HSC emergence in a non-cell-autonomous manner. Epistatic analyses demonstrate that Notch3 function lies downstream of Wnt16, which is required for HSC specification through its regulation of two Notch ligands, dlc and dld. Collectively, these findings demonstrate for the first time that multiple Notch signaling inputs are required to specify HSCs and that Notch3 performs a novel role within the somite to regulate the neighboring precursors of hemogenic endothelium.  
  Call Number Serial 1048  
Permanent link to this record
 

 
Author (up) Kobayashi, I.; Kobayashi-Sun, J.; Kim, A.D.; Pouget, C.; Fujita, N.; Suda, T.; Traver, D. file  url
openurl 
  Title Jam1a-Jam2a interactions regulate haematopoietic stem cell fate through Notch signalling Type Journal Article
  Year 2014 Publication Nature Abbreviated Journal Nature  
  Volume 512 Issue 7514 Pages 319-323  
  Keywords Animals; Aorta/cytology/growth & development/metabolism; Cell Differentiation; Cell Movement; Hematopoietic Stem Cells/*cytology/*metabolism; Junctional Adhesion Molecule A/genetics/*metabolism; Junctional Adhesion Molecule B/genetics/*metabolism; Phenotype; Receptors, Cell Surface/genetics/*metabolism; Receptors, Notch/*metabolism; *Signal Transduction; Somites/cytology/embryology/metabolism; Zebrafish/embryology/*metabolism; Zebrafish Proteins/genetics/*metabolism  
  Abstract Notch signalling plays a key role in the generation of haematopoietic stem cells (HSCs) during vertebrate development and requires intimate contact between signal-emitting and signal-receiving cells, although little is known regarding when, where and how these intercellular events occur. We previously reported that the somitic Notch ligands, Dlc and Dld, are essential for HSC specification. It has remained unclear, however, how these somitic requirements are connected to the later emergence of HSCs from the dorsal aorta. Here we show in zebrafish that Notch signalling establishes HSC fate as their shared vascular precursors migrate across the ventral face of the somite and that junctional adhesion molecules (JAMs) mediate this required Notch signal transduction. HSC precursors express jam1a (also known as f11r) and migrate axially across the ventral somite, where Jam2a and the Notch ligands Dlc and Dld are expressed. Despite no alteration in the expression of Notch ligand or receptor genes, loss of function of jam1a led to loss of Notch signalling and loss of HSCs. Enforced activation of Notch in shared vascular precursors rescued HSCs in jam1a or jam2a deficient embryos. Together, these results indicate that Jam1a-Jam2a interactions facilitate the transduction of requisite Notch signals from the somite to the precursors of HSCs, and that these events occur well before formation of the dorsal aorta.  
  Call Number Serial 1046  
Permanent link to this record
 

 
Author (up) Nguyen, P.D.; Hollway, G.E.; Sonntag, C.; Miles, L.B.; Hall, T.E.; Berger, S.; Fernandez, K.J.; Gurevich, D.B.; Cole, N.J.; Alaei, S.; Ramialison, M.; Sutherland, R.L.; Polo, J.M.; Lieschke, G.J.; Currie, P.D. file  url
doi  openurl
  Title Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1 Type Journal Article
  Year 2014 Publication Nature Abbreviated Journal Nature  
  Volume 512 Issue 7514 Pages 314-318  
  Keywords Animals; Aorta/cytology/embryology; Biological Markers/analysis; Cell Movement; Chemokine CXCL12/analysis/metabolism; Chick Embryo; Endothelial Cells/*cytology/metabolism; Hematopoietic Stem Cells/*cytology/metabolism; Homeodomain Proteins/analysis/genetics/*metabolism; Humans; Mice; Muscles/cytology/metabolism; Mutation/genetics; Somites/*cytology/metabolism; Transcription Factors/analysis/genetics/*metabolism; Wnt Proteins/analysis/metabolism; Zebrafish/embryology/metabolism; Zebrafish Proteins/analysis/genetics/*metabolism  
  Abstract Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the DA generates a dramatic increase in chemokine-dependent HSC induction. This study reveals the molecular basis for a novel somite lineage restriction mechanism and defines a new paradigm in induction of definitive HSCs.  
  Call Number Serial 1047  
Permanent link to this record
 

 
Author (up) Prabhu, V.V.; Hong, B.; Allen, J.E.; Zhang, S.; Lulla, A.R.; Dicker, D.T.; El-Deiry, W.S. file  url
openurl 
  Title Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated DeltaNp73 Inhibition and p73 Activation Type Journal Article
  Year 2016 Publication Cancer Research Abbreviated Journal Cancer Res  
  Volume 76 Issue 7 Pages 1989-1999  
  Keywords p53; Tumor suppression; p73; Colorectal cancer; Stem cells  
  Abstract Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer. In contrast, p53 family member p73 is rarely mutated in colorectal cancer and p73 activation elicits p53-like tumor suppression. Colorectal cancer stem cells (CRCSC) comprise a rare self-renewing subpopulation that contributes to tumor maintenance and chemoresistance. p53 restoration is known to target CRCSCs, but p73 restoration in CRCSCs has not been examined. In this study, we investigated the effects of the small-molecule prodigiosin, which restores the p53 pathway in tumor cells via p73 activation, on CRCSCs in vitro and in vivo Prodigiosin prevented colonosphere formation independent of p53 status and reduced the viability of self-renewing, 5-fluorouracil-resistant Aldefluor positive [Aldefluor(+)] CRCSCs in vitro Furthermore, prodigiosin inhibited the growth of xenograft tumors initiated with Aldefluor+ cells without toxic effects and limited the tumorigenic potential of these cells. Consistently, prodigiosin induced activation of a p53-responsive luciferase reporter in colonospheres, Aldefluor(+) cells, and tumor xenografts. Mechanistic studies revealed that prodigiosin increased the levels of p73 and reduced levels of the oncogenic N-terminally truncated isoform DeltaNp73 in Aldefluor(+) cells. Accordingly, p73 knockdown or DeltaNp73 overexpression suppressed prodigiosin-mediated inhibition of colonosphere formation. Moreover, prodigiosin increased levels of the transcription factor c-Jun, a regulator of p73 and DeltaNp73, in both the cytoplasm and nucleus. c-Jun knockdown attenuated prodigiosin-mediated p53-reporter activation, DeltaNp73 downregulation, p73 activation, and cell death. Collectively, our findings highlight the previously uncharacterized use of p73-activating therapeutics to target CRCSCs.  
  Call Number Serial 1518  
Permanent link to this record
 

 
Author (up) Sahin, I.H.; Iacobuzio-Donahue, C.A.; O'Reilly, E.M. file  url
openurl 
  Title Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy Type Journal Article
  Year 2016 Publication Expert Opinion on Therapeutic Targets Abbreviated Journal Expert Opin Ther Targets  
  Volume 20 Issue 3 Pages 341-359  
  Keywords K-Ras pathway; Wnt signaling; cancer stem cells; expression signature; molecular pathways; notch signaling; p53; pancreatic cancer; targeted treatment  
  Abstract INTRODUCTION: Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting. AREAS COVERED: In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-beta signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment. EXPERT OPINION: Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a 'precision medicine' approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes.  
  Call Number Serial 1505  
Permanent link to this record
Select All    Deselect All
 |   | 
Details
   print

Save Citations: