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1.
Development ; 129(14): 3513-22, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12091320

ABSTRACT

PTEN is a tumour suppressor gene involved in cell cycle control, apoptosis and mediation of adhesion and migration signalling. Germline mutations of PTEN in humans are associated with familial tumour syndromes, among them Cowden disease. Glioblastomas, highly malignant glial tumours of the central nervous system frequently show loss of PTEN. Recent reports have outlined some aspects of PTEN function in central nervous system development. Using a conditional gene disruption approach, we inactivated Pten in mice early during embryogenesis locally in a region specific fashion and later during postnatal development in a cell-specific manner, to study the role of PTEN in differentiation, migration and neoplastic transformation. We show that PTEN is required for the realisation of normal cerebellar architecture, for regulation of cell and organ size, and for proper neuronal and glial migration. However, PTEN is not required for cell differentiation and lack of PTEN is not sufficient to induce neoplastic transformation of neuronal or glial cells


Subject(s)
Cell Movement , Cerebellar Neoplasms/etiology , Cerebellum/cytology , Cerebellum/embryology , Phosphoric Monoester Hydrolases/physiology , Protein Serine-Threonine Kinases , Tumor Suppressor Proteins/physiology , Animals , Cell Cycle Proteins/metabolism , Cell Death/genetics , Cell Differentiation/genetics , Cell Movement/genetics , Cell Transformation, Neoplastic/genetics , Cerebellum/metabolism , Cyclin-Dependent Kinase Inhibitor p27 , Gene Targeting , Genes, Tumor Suppressor , Humans , Mice , Mice, Mutant Strains , Mice, Transgenic , PTEN Phosphohydrolase , Phosphoric Monoester Hydrolases/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
2.
FASEB J ; 16(3): 411-3, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11790723

ABSTRACT

In the first-trimester mammalian fetus, skin wounds heal with perfect reconstitution of the dermal architecture without scar formation. Understanding environmental molecular regulation in fetal wound healing may reveal scar-limiting therapeutical strategies for the prevention of postnatal scarring wound repair. Therefore, we performed studies on fetal skin oxygenation and skin and wound expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in the sheep model in vivo and performed studies on the potential relevance of HIF-1alpha during wound healing in vitro. Skin oxygen partial pressure levels were hypoxic throughout normal development. In nonscarring fetal skin at gestation day (GD)60, HIF-1alpha could be detected neither in healthy nor in wounded tissue. At GD100, in wounds with minimal scar formation, HIF-1alpha was expressed in fibroblasts and was markedly up-regulated at the wound edge. In scarring fetal wounds at GD120, HIF-1alpha was predominantly expressed in inflammatory cells. Expression of transforming growth factor beta3 (TGF-beta3), a potent antiscarring cytokine, overlapped with HIF-1a expression at GD100. HIF-1alpha-deficient mouse embryonic fibroblasts showed impaired migratory capabilities and demonstrated that TGF-beta3, but not proscarring TGF-beta1, manifests hypoxia- and HIF-1alpha-dependent regulation. In conclusion, HIF-1alpha-dependent regulation of a potent antiscarring cytokine may provide new strategies for antiscarring manipulation of wound healing.


Subject(s)
DNA-Binding Proteins/biosynthesis , Fetus/physiology , Nuclear Proteins/biosynthesis , Skin/embryology , Transcription Factors , Transforming Growth Factor beta/biosynthesis , Wound Healing , Animals , Cell Hypoxia , Cell Movement , Cells, Cultured , DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Fetus/anatomy & histology , Fibroblasts/physiology , Hypoxia-Inducible Factor 1 , Hypoxia-Inducible Factor 1, alpha Subunit , Immunohistochemistry , Mice , Models, Biological , Nuclear Proteins/genetics , Nuclear Proteins/physiology , Sheep , Skin/metabolism , Skin Diseases/genetics , Skin Diseases/metabolism , Transcriptional Activation , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta3
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