Tissue stem cells and germ line or embryonic stem cells were shown to have reduced oxidative metabolism, which was proposed to be an adaptive mechanism to reduce damage accumulation caused by reactive oxygen species. However, an alternate explanation is that stem cells are less dependent on specialized cytoplasmic functions compared with differentiated cells, therefore, having a high nuclear-to-cytoplasmic volume ratio and consequently a low mitochondrial content. To determine whether stem cells rely or not on mitochondrial respiration, we selectively ablated the electron transport chain in the basal layer of the epidermis, which includes the epidermal progenitor/stem cells (EPSCs). This was achieved using a loxP-flanked mitochondrial transcription factor A (Tfam) allele in conjunction with a keratin 14 Cre transgene. The epidermis of these animals (Tfam EKO ) showed a profound depletion of mitochondrial DNA and complete absence of respiratory chain complexes. However, despite a short lifespan due to malnutrition, epidermal development and skin barrier function were not impaired. Differentiation of epidermal layers was normal and no proliferation defect or major increase of apoptosis could be observed. In contrast, mice with an epidermal ablation of prohibitin-2, a scaffold protein in the inner mitochondrial membrane, displayed a dramatic phenotype observable already in utero, with severely impaired skin architecture and barrier function, ultimately causing death from dehydration shortly after birth. In conclusion, we here provide unequivocal evidence that EPSCs, and probably tissue stem cells in general, are independent of the mitochondrial respiratory chain, but still require a functional dynamic mitochondrial compartment.
Bone morphogenetic protein 7 (BMP-7) belongs to the superfamily of transforming growth factor β-like cytokines, which can act either as tumor suppressors or as tumor promoters depending on cell type and differentiation. Our investigations focused on analyzing the effects of BMP-7 during glioma cell proliferation in vitro and in vivo. BMP-7 treatment decreased the proliferation of Gli36ΔEGFR-LITG glioma cells up to 50%through a cell cycle arrest in the G(1) phase but not by induction of apoptosis. This effect was mediated by the modulation of the expression and phosphorylation of cyclin-dependent kinase 2, cyclin-dependent kinase inhibitor p21, and downstream retinoblastoma protein. Furthermore, in vivo optical imaging of luciferase activity of Gli36ΔEGFR-LITG cells implanted intracranially into nude mice in the presence or absence of BMP-7 treatment corroborated the antiproliferative effects of this cytokine. This report clearly underlines the tumor-suppressive role of BMP-7 in glioma-derived cells. Taken together, our results indicate that manipulating the BMP/transforming growth factor β signaling cascade may serve as a new strategy for imaging-guided molecular-targeted therapy of malignant gliomas.
Metastasis of malignant tumor cells involves cell-cell and cellmatrix interactions, which regulate the expression and localization of proteolytic enzymes. In the present study, we investigated the expression and localization of the lysosomal cysteine proteinase cathepsin B and its natural inhibitors cystatin A, B and C in high-(MV3), intermediate-(SKmel28) and low-invasive (SKmel23, WM164) human melanoma cell lines grown on plastic or in contact with monomeric or fibrillar collagen type I. Neither the transcript levels of cathepsin B nor those of the natural inhibitors, cystatin B and C, were altered by the interaction of melanoma cells with collagen type I. However, protein expression and cellular localization of cathepsin B and its inhibitors were markedly affected. In contrast to low-invasive cells, high-invasive cells constitutively released procathepsin B when cultured on plastic. In addition, contact of invasive cells with fibrillar collagen type I resulted in the release of both mature forms of the protease. Perturbation studies using inhibitory antibodies against the b1 subunit of the integrin receptor indicated a role for the b1 integrin receptor family in the regulation of cathepsin B release. Cystatin B protein expression was much lower in high-invasive cells in both culture conditions, when compared to low-invasive cells. Cystatin C expression was comparable in all cells, but cell contact to fibrillar collagen type I induced its expression. These results strongly implicate a pivotal role of cell-matrix interactions for the regulation of cathepsin B localization and activity in melanoma cells. ' 2005 Wiley-Liss, Inc.Key words: cathepsin B; extracellular matrix; melanoma; cystatins Tumor invasion and metastasis are multistep processes, which include tumor-host interactions mediated by cell-cell and cellmatrix contacts. 1 To invade adjacent tissue and metastasize, tumor cells have to cross various extracellular barriers like extracellular matrix (ECM), basement membranes and interstitial stroma. Degradation of ECM components and remodeling of connective tissue and basement membranes requires the concerted action of various classes of intra-and/or extracellular proteases. 2 These include serine proteases (plasmin, tissue-type plasminogen activator, urokinase-type plasminogen activator and Cat G), matrix metalloproteases (MMP-2, -9, -1, -7, -3 and MT1-MMP), aspartic proteases (Cat D) and cysteine proteases (Cat B, H and L). [3][4][5][6][7][8] Cat B (EC 3.4.22.16) is a lysosomal cysteine protease of the papain family of proteases, 9 which is also involved in a number of disease processes, such as osteoarthritis 10,11 and rheumatoid arthritis. 12 This enzyme has also been shown to be involved in tumor invasion and metastasis. Increase in Cat B activity or upregulation of transcripts/protein expression was found in various types of carcinomas, like breast, 13 lung, 14 gastrointestinal 15 and urogenital 16,17 carcinomas. In addition, Cat B has also been shown to be overexpressed in chondrosarcomas, 18 glioma...
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