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1.
Oncogene ; 29(18): 2724-38, 2010 May 06.
Article in English | MEDLINE | ID: mdl-20208566

ABSTRACT

Microenvironmental clues are critical to cell behavior. One of the key elements of migration is the generation and response to forces. Up to now, there is no definitive concept on how the generation and responses to cellular forces influence cancer-cell behavior. Here, we show that expression of receptor-type tyrosine-protein phosphatase alpha (RPTPalpha) in human SW480 colon cancer cells sets a threshold for the response to matrix forces by changing cellular contractility. This can be explained as an RPTPalpha-mediated increase in contractility with a consecutive increase in number and size of adhesion sites and stress fibers. These effects are mediated through myosin light chain kinase and largely independent of Rho/Rho-kinase (ROCK) signaling. In addition, we report that RPTPalpha influences spreading on low-rigidity surfaces, binding of collagen-coated beads and expression of RPTPalpha is required for invasion into the chorioallantoic membrane. These data suggest that force-responsive proteins such as RPTPalpha can influence cancer-cell behavior and identify potential targets for cancer therapy.


Subject(s)
Colonic Neoplasms/pathology , Cytoskeleton/physiology , Receptor-Like Protein Tyrosine Phosphatases, Class 4/physiology , Cell Adhesion , Cell Line, Tumor , Elasticity , Humans , Muscle Contraction , Myosin-Light-Chain Kinase/physiology , Neoplasm Invasiveness , rho-Associated Kinases/physiology , src-Family Kinases/physiology
2.
Oncogene ; 26(40): 5939-49, 2007 Aug 30.
Article in English | MEDLINE | ID: mdl-17369846

ABSTRACT

Recently, we identified the homeodomain transcription factor CUTL1 as important mediator of cell migration and tumor invasion downstream of transforming growth factor beta (TGFbeta). The molecular mechanisms and effectors mediating the pro-migratory and pro-invasive phenotype induced by CUTL1 have not been elucidated so far. Therefore, the aim of this study was to identify signaling pathways downstream of CUTL1 which are responsible for its effects on tumor cell migration. We found that the reduced motility seen after knock down of CUTL1 by RNA interference is accompanied by a delay in tumor cell spreading. This spreading defect is paralleled by a marked reduction of Src protein levels. We show that CUTL1 leads to Src protein stabilization and activation of Src-regulated downstream signaling molecules such as RhoA, Rac1, Cdc42 and ROCK. In addition, we demonstrate that CUTL1 decreases proteasome-mediated Src protein degradation, possibly via transcriptionally upregulating C-terminal Src kinase (Csk). Based on experiments using Src knockout cells (SYF), we present evidence that Src plays a crucial role in CUTL1-induced tumor cell migration. In conclusion, our findings linking the pro-invasive transcription factor CUTL1 and the Src pathway provide important new insights in the molecular effector pathways mediating CUTL-induced migration and invasion.


Subject(s)
Gene Expression Regulation, Neoplastic , Homeodomain Proteins/physiology , Neoplasms/metabolism , Nuclear Proteins/physiology , Proteasome Endopeptidase Complex/metabolism , Repressor Proteins/physiology , src-Family Kinases/metabolism , CSK Tyrosine-Protein Kinase , Cell Adhesion , Cell Line, Tumor , Cell Movement , Homeodomain Proteins/metabolism , Humans , Models, Biological , Neoplasm Invasiveness , Nuclear Proteins/metabolism , Phenotype , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Repressor Proteins/metabolism , Signal Transduction , Transcription Factors , Transcription, Genetic
3.
Acta Neurol Scand ; 111(4): 274-7, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15740580

ABSTRACT

OBJECTIVES: Analysis of the CTG-repeat number and three biallelic markers, Alu(+/-), HinfI(+/-), and TaqI(+/-), in the DMPK gene in healthy and myotonic dystrophy type 1 (DM1) Serbian individuals. Also, the consideration of haplotypes in the light of the proposed models of CTG-repeat evolution and origin of the DM1 mutation. MATERIALS AND METHODS: Markers were analyzed by PCR and haplotypes were obtained on 203 unrelated normal chromosomes and 24 unrelated DM1 chromosomes. RESULTS: A strong linkage disequilibrium was detected between the three biallelic markers alone (P <0.0001) and between distinct CTG-repeat size classes and reconstructed haplotypes. Greater than 98% of normal chromosomes contain (+++) and (- - -) haplotypes. The (+++) haplotype is the most common, while the (CTG)(9-17) are the most frequent alleles. We found a complete association of (+++) haplotype with (CTG)(> or =18) and mutated alleles. CONCLUSIONS: (CTG)(9-17)/(+++) haplotype is the ancestral haplotype and DM1 mutation occurred on (CTG)(18-35)/+++ chromosome.


Subject(s)
Myotonic Dystrophy/genetics , Protein Serine-Threonine Kinases/genetics , Case-Control Studies , Female , Genetic Markers , Haplotypes , Humans , Male , Myotonin-Protein Kinase , Pedigree , Trinucleotide Repeats , Yugoslavia
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