Cancer genetics: mouse models of intestinal cancer

2007 ◽  
Vol 35 (5) ◽  
pp. 1338-1341 ◽  
Author(s):  
A.R. Clarke
Keyword(s):  
Target Genes ◽  
Cancer Genetics ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Control Of Gene Expression ◽  
Approaches To Study ◽  
Temporal And Spatial

The capacity to model cancer within the mouse has advanced significantly in recent years. Perhaps the most notable technical gains have been in the development of techniques that allow the temporal and spatial control of gene expression, so that it is now possible to regulate target genes in the tissue of choice and at a given time [Maddison and Clarke (2005) J. Pathol. 205, 181–193; Shaw and Clarke (2007) DNA Repair 6, 1403–1412; Marsh and Clarke (2007) Expert Rev. Anticancer Ther. 7, 519–531]. We have used these approaches to study tumorigenesis in the murine intestine. Loss of function of the tumour-suppressor gene Apc (adenomatous polyposis coli) has been associated with the development of both human and murine neoplasia, principally those of the intestinal epithelium. However, as Apc has been implicated in multiple cellular functions, the precise mechanisms underlying these associations remain somewhat unclear. I review here the use of an inducible strategy to co-ordinately delete genes from the adult murine epithelium. This approach has allowed a characterization of the direct consequences of inactivation of gene function. For Apc, these include failure in the differentiation programme, failure to migrate, aberrant proliferation and the aberrant induction of apoptosis. Transcriptome analysis of this model has also identified potential new targets for therapeutic intervention, such as Sparc (secreted protein acidic and rich in cysteine), deficiency of which, we have now shown, suppresses adenoma formation. Finally, we have been able to address how other genes modulate the consequences of Apc loss. Thus we show that there is little effect following loss of cyclin D1, Tcf-1 and p53, but that there are marked differences following loss of either c-Myc or Mbd2. The models therefore allow us to define the earliest events associated with carcinogenesis in the intestine.

scholarly journals Expression of lamina proteins Lamin Dm0 and Kugelkern suppresses stem cell proliferation

2017 ◽  
Author(s):  
Roman Petrovsky ◽  
Jörg Großhans
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Target Genes ◽  
Cell Function ◽  
Nuclear Lamina ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Stem Cell Proliferation ◽  
Wide Range ◽  
Nuclear Stability

AbstractThe nuclear lamina is involved in numerous cellular functions, such as gene expression, nuclear organization, nuclear stability, and cell proliferation. The mechanism underlying the involvement of lamina is often not clear, especially in physiological contexts. Here we investigate how the farnesylated lamina proteins Lamin Dm0 and Kugelkern are linked to proliferation control of intestinal stem cells (ISCs) in adult Drosophila flies by loss-of-function and gain-of-function experiments. We found that ISCs mutant for Lamin Dm0 or Kugelkern proliferate, whereas overexpression of Lamin Dm0 or Kugelkern strongly suppressed proliferation. The anti-proliferative activity is, at least in part, due to suppression of Jak/Stat but not Delta/Notch signalling. Lamin Dm0 expression suppresses Jak/Stat signalling by normalization of about 50% of the Stat target genes in ISCs.Author summaryThe nuclear lamina is a protein meshwork that lies beneath the inner side of the nuclear membrane and interacts with nuclear pores, chromatin and the cytoskeleton. Changes in proteins of the nuclear lamina cause a wide range of diseases which are often not well understood. It is hypothesized that impairment of stem cell function, as a result of lamina changes, might play a key role in some of those diseases. Here we use the well characterized Drosophila midgut as a system to investigate the role of lamina proteins Lamin Dm0 and Kugelkern on stem cell proliferation.

scholarly journals Golgi stress–induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing

2018 ◽  
Vol 29 (1) ◽  
pp. 42-52 ◽  
Author(s):  
Jan Baumann ◽  
Tatiana I. Ignashkova ◽  
Sridhar R. Chirasani ◽  
Silvia Ramírez-Peinado ◽  
Hamed Alborzinia ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Stress Responses ◽  
Secretory Pathway ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Mapk Signaling ◽  
Gene Set Enrichment Analysis ◽  
Loss Of Function ◽  
Control Of Gene Expression ◽  
Ets Family

The secretory pathway is a major determinant of cellular homoeostasis. While research into secretory stress signaling has so far mostly focused on the endoplasmic reticulum (ER), emerging data suggest that the Golgi itself serves as an important signaling hub capable of initiating stress responses. To systematically identify novel Golgi stress mediators, we performed a transcriptomic analysis of cells exposed to three different pharmacological compounds known to elicit Golgi fragmentation: brefeldin A, golgicide A, and monensin. Subsequent gene-set enrichment analysis revealed a significant contribution of the ETS family transcription factors ELK1, GABPA/B, and ETS1 to the control of gene expression following compound treatment. Induction of Golgi stress leads to a late activation of the ETS upstream kinases MEK1/2 and ERK1/2, resulting in enhanced ETS factor activity and the transcription of ETS family target genes related to spliceosome function and cell death induction via alternate MCL1 splicing. Further genetic analyses using loss-of-function and gain-of-function experiments suggest that these transcription factors operate in parallel.

scholarly journals Playing Tag with HIF: The VHL Story

2002 ◽  
Vol 2 (3) ◽  
pp. 131-135 ◽  
Author(s):  
Sherri K. Leung ◽  
Michael Ohh
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
E3 Ubiquitin Ligase ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Matrix Assembly ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex

Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL is the cause of inherited VHL disease and is associated with sporadic kidney cancer. pVHL is found in a multiprotein complex with elongins B/C, Cul2, and Rbx1 forming an E3 ubiquitin ligase complex called VEC. This modular enzyme targets theαsubunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated destruction. Consequently, tumour cells lacking functional pVHL overproduce the products of HIF-target genes such as vascular endothelial growth factor (VEGF), which promotes angiogenesis. This likely accounts for the hypervascular nature of VHL-associated neoplasms. Although pVHL has been linked to the cell-cycle, differentiation, and the regulation of extracellular matrix assembly, microenvironment pH, and tissue invasiveness, this review will focus on the recent insights into the molecular mechanisms governing the E3 ubiquitin ligase function of VEC.

A Systematic Screen for Dominant Second-Site Modifiers of Merlin/NF2 Phenotypes Reveals an Interaction With blistered/DSRF and scribbler

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 667-679
Author(s):  
Dennis R LaJeunesse ◽  
Brooke M McCartney ◽  
Richard G Fehon
Keyword(s):  
Human Tumor ◽  
Suppressor Gene ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Genetic Screens ◽  
Cellular Functions ◽  
Cell Proliferation And Differentiation ◽  
Epithelial Development ◽  
Proliferation And Differentiation ◽  
Neuronal Tissues

Abstract Merlin, the Drosophila homologue of the human tumor suppressor gene Neurofibromatosis 2 (NF2), is required for the regulation of cell proliferation and differentiation. To better understand the cellular functions of the NF2 gene product, Merlin, recent work has concentrated on identifying proteins with which it interacts either physically or functionally. In this article, we describe genetic screens designed to isolate second-site modifiers of Merlin phenotypes from which we have identified five multiallelic complementation groups that modify both loss-of-function and dominant-negative Merlin phenotypes. Three of these groups, Group IIa/scribbler (also known as brakeless), Group IIc/blistered, and Group IId/net, are known genes, while two appear to be novel. In addition, two genes, Group IIa/scribbler and Group IIc/blistered, alter Merlin subcellular localization in epithelial and neuronal tissues, suggesting that they regulate Merlin trafficking or function. Furthermore, we show that mutations in scribbler and blistered display second-site noncomplementation with one another. These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development.

SGK1 mutations in DLBCL generate hyperstable protein neoisoforms that promote AKT independence.

Blood ◽  
2021 ◽  
Author(s):  
Jie Gao ◽  
Eirini Sidiropoulou ◽  
Ieuan Walker ◽  
Joanna Alicja Krupka ◽  
Karol Mizielinski ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
B Cell Lymphoma ◽  
Suppressor Gene ◽  
Kinase Domain ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Protein Isoforms ◽  
Loss Of Function ◽  
Over Expression ◽  
Frequent Finding

Serum and Glucocorticoid-regulated Kinase-1 (SGK1) is one of the most frequently mutated genes in Diffuse Large B Cell Lymphoma (DLBCL). However, little is known about its function or the consequence of its mutation. The frequent finding of truncating mutations has led to the widespread assumption that these represent loss-of-function variants and accordingly, that SGK1 must act as a tumour suppressor. Here we show that instead, the most common SGK1 mutations lead to production of aberrantly spliced mRNA neoisoforms in which translation is initiated from downstream methionines. The resulting N-terminal truncated protein isoforms show increased expression due to the exclusion of an N-terminal degradation domain. However, they retain a functional kinase domain, the over-expression of which renders cells resistant to AKT inhibition in part due to increased phosphorylation of GSK3B. These findings challenge the prevailing assumption that SGK1 is a tumour suppressor gene in DLBCL and provide the impetus to explore further the pharmacological inhibition of SGK1 as a therapeutic strategy for DLBCL.

scholarly journals Characterization of the imprinted polycomb gene L3MBTL , a candidate 20q tumour suppressor gene, in patients with myeloid malignancies

2004 ◽  
Vol 127 (5) ◽  
pp. 509-518 ◽  
Author(s):  
Anthony J. Bench ◽  
Juan Li ◽  
Brian J. P. Huntly ◽  
Eric Delabesse ◽  
Nasios Fourouclas ◽  
...  
Keyword(s):  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Myeloid Malignancies

Isolation and Partial Characterization of Potential Melanoma Suppressor Genes Using a Novel Subtractive Melanocyte Library

1997 ◽  
Vol 1 (3) ◽  
pp. 132-136
Author(s):  
Victor A. Tron ◽  
Martin J. Trotter ◽  
Vincent C. Ho
Keyword(s):  
Skin Diseases ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Cdna Clones ◽  
Subtractive Library ◽  
Wide Range ◽  
Fused Gene ◽  
Tyrosinase Related Protein

Background: There is increasing evidence that a tumour suppressor plays a role in the pathogenesis of cutaneous melanoma. Objective: Our objective was to isolate a melanoma-tumour suppressor gene. Methods: We constructed a novel subtractive library enriched for cDNAs expressed preferentially in normal melanocytes. Candidate genes were isolated using differential hybridization and were characterized further by Northern blot analysis. Results: Initially, 238 plaques were isolated, of which 57 contained insert cDNA. Ten of the cDNA clones demonstrated expression in normal melanocytes and were not present in at least one of four melanoma cell lines. Three of the clones showed no expression in melanocytes, but did hybridize with at least one of the melanoma lines. The remaining 44 clones were not expressed in either melanocyte or melanoma lines. Partial DNA sequence analysis of four selected clones revealed a cDNA representing the Ret Fused Gene (RFG) and two others highly homologous to tyrosinase-related protein (TRP1). Ret Fused Gene, a gene originally isolated from thyroid gland tumours, has been mapped to chromosome 10, whereas the TRP1 has been mapped to chromosome 9p. Both these genetic loci are known to be altered in melanoma. Conclusion: The method used is a powerful tool for the identification of genes important in the pathogenesis of skin diseases and is applicable to the study of a wide range of neoplastic and nonneoplastic conditions.

Current View of miRNA with Tumor Suppressor Function, Exploring MDS and AML as Models

2014 ◽  
Vol 3 ◽  
pp. STI.S12316
Author(s):  
Nicholas Iverson ◽  
Naomi Galili ◽  
Abdullah M. Ali ◽  
Azra Raza
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Current View ◽  
Murine Models ◽  
Tumor Suppressor Function ◽  
Cellular Functions ◽  
Control Of Gene Expression ◽  
The Past

Since the discovery of microRNAs (miRNAs) in 1993, their role in controlling a wide variety of complex and seminal cellular functions through control of gene expression continues to be elucidated. Studies of the past decade have shown that miRNAs are able to activate or suppress target genes that are key players in the molecular pathways found to be deregulated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The ability of miRNAs to act as tumor suppressor genes has been demonstrated in a number of studies in both human samples and cell lines as well as in murine models of AML and MDS. The focus of this review will be to examine the complex interaction of specific miRNAs with genes that have been implicated in MDS/AML and which may eventually become therapeutically relevant.

Sign in / Sign up

Export Citation Format

Share Document