Abstract. The ot6//34 complex is a member of the integrin family of adhesion receptors. It is found on a variety of epithelial cell types, but is most strongly expressed on stratified squamous epithelia. Fluorescent antibody staining of human epidermis suggests that the /~4 subunit is strongly localized to the basal region showing a similar distribution to that of the 230-kD bullous pemphigoid antigen. The or6 subunit is also strongly localized to the basal region but in addition is present over the entire surfaces of basal cells and some cells in the immediate suprabasal region. By contrast staining for ~31, o~2, and o~3 subunits was very weak basally, but strong on all other surfaces of basal epidermal cells. These results suggest that different integrin complexes play differing roles in cell-cell and cell-matrix adhesion in the epidermis.Immunoelectron microscopy showed that the a6/~4 complex at the basal epidermal surface is strongly localized to hemidesmosomes. This result provides the first well-characterized monoclonal antibody markers for hemidesmosomes and suggests that the ot6//34 complex plays a major role in epidermal cell-basement membrane adhesion. We suggest that the cytoplasmic domains of these transmembrane glycoproteins may contribute to the structure of hemidesmosomal plaques. Immunoultrastructural localization of the BP antigen suggests that it may be involved in bridging between hemidesmosomal plaques and keratin intermediate filaments of the cytoskeleton.
BackgroundThe possibility to combine Low Intensity UltraSound (LIUS) and Nanoparticles (NP) could represent a promising strategy for drugs delivery in tumors difficult to treat overcoming resistance to therapies. On one side the NP can carry drugs that specifically target the tumors on the other the LIUS can facilitate and direct the delivery to the tumor cells. In this study, we investigated whether Very Low Intensity UltraSound (VLIUS), at intensities lower than 120 mW/cm2, might constitute a novel strategy to improve delivery to tumor cells. Thus, in order to verify the efficacy of this novel modality in terms of increase selective uptake in tumoral cells and translate speedily in clinical practice, we investigated VLIUS in three different in vitro experimental tumor models and normal cells adopting three different therapeutic strategies.MethodsVLIUS at different intensities and exposure time were applied to tumor and normal cells to evaluate the efficiency in uptake of labeled human ferritin (HFt)-based NP, the delivery of NP complexed Firefly luciferase reported gene (lipoplex-LUC), and the tumor-killing of chemotherapeutic agent.ResultsSpecifically, we found that specific VLIUS intensity (120 mW/cm2) increases tumor cell uptake of HFt-based NPs at specific concentration (0.5 mg/ml). Similarly, VLIUS treatments increase significantly tumor cells delivery of lipoplex-LUC cargos. Furthermore, of interest, VLIUS increases tumor killing of chemotherapy drug trabectedin in a time dependent fashion. Noteworthy, VLIUS treatments are well tolerated in normal cells with not significant effects on cell survival, NPs delivery and drug-induced toxicity, suggesting a tumor specific fashion.ConclusionsOur data shed novel lights on the potential application of VLIUS for the design and development of novel therapeutic strategies aiming to efficiently deliver NP loaded cargos or anticancer drugs into more aggressive and unresponsive tumors niche.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-1018-6) contains supplementary material, which is available to authorized users.
We previously demonstrated that  4 integrin subunit overexpression increases in vitro invasiveness of NIH3T3 cells that have been transformed by ErbB-2 oncogene. We used this model to identify domains within the large  4 cytoplasmic domain that are involved in the interaction of ␣ 6  4 with ErbB-2, invasion, and phosphatidylinositol 3-kinase (PI3K) activation. For this purpose, we expressed deletion mutants of  4 that lacked either all or portions of the  4 cytoplasmic domain in NIH3T3/ErbB-2 cells. We also used an ecto-domain mutant in which most of the extracellular domain of  4 was replaced with a c-Myc tag. These transfectants were examined for their ability to invade Matrigel and their ability to activate PI3K, as well as for the ability of ␣ 6  4 to co-immunoprecipitate with ErbB-2. The results obtained revealed that a region of the  4 cytoplasmic domain between amino acids 854 and 1183 is critical for the ability of ␣ 6  4 integrin to increase invasion. Interestingly, the extracellular domain of  4 is not necessary for ␣ 6  4 to stimulate invasion. The association of ␣ 6  4 with ErbB-2 is dependent upon the  4 cytoplasmic domain and can occur in the absence of ␣ 6  4 heterodimerization. Finally, we observed strong activation of PI3K with  4 wild type and with those  4 deletion mutants that were able to stimulate invasion upon the expression in NIH3T3/ErbB-2 cells. In conclusion, our results establish that there is cooperation between ␣ 6  4 and ErbB-2 in promoting PI3K-dependent invasion and implicate a specific region of the  4 cytoplasmic domain (amino acids 854 -1183) in this event.Integrins are the major family of cell surface receptors that mediate attachment to the extracellular matrix. The interaction between integrins and their ligands is involved in the regulation of many cellular functions, including embryonic development, cell proliferation, as well as tumor growth and metastasis. Integrins are composed of ␣ and  transmembrane subunits that heterodimerize to form different receptors. A single ␣ subunit (e.g. ␣ v or ␣ 6 ) can associate with different  subunits, ( 1 ,  3 ,  5 , or  1 ,  4 , respectively), promoting different ligand binding specificity (1-3). The ␣ 6  4 integrin is a receptor for various isoforms of the basement membrane component laminin (4 -6), and its expression is restricted to epithelia, endothelia and peripheral nerves (7-9). In many epithelia, ␣ 6  4 is found in hemidesmosomes where it plays an essential role in their organization (10,11). This integrin can also interact with F-actin and promote the migration of invasive carcinoma cells (12, 13).The intracellular portion of the  4 subunit is much larger (1,000 amino acids) than that of all the other known  subunits, and it does not exhibit apparent sequence homology with them (14 -16). Increasing evidence indicates that the ability of ␣ 6  4 to regulate cell proliferation, motility, and invasion is dependent upon signal transduction events that are mediated by the  4 cytoplasmic domain (17-19)...
Proper regulation of white and brown adipogenic differentiation is important for maintaining an organism's metabolic profile in a homeostatic state. The recent observations showing that the p53 tumor suppressor plays a role in metabolism raise the question of whether it is involved in the regulation of white and brown adipocyte differentiation. By using several in vitro models, representing various stages of white adipocyte differentiation, we found that p53 exerts a suppressive effect on white adipocyte differentiation in both mouse and human cells. Moreover, our in vivo analysis indicated that p53 is implicated in protection against diet-induced obesity. In striking contrast, our data shows that p53 exerts a positive regulatory effect on brown adipocyte differentiation. Abrogation of p53 function in skeletal muscle committed cells reduced their capacity to differentiate into brown adipocytes and histological analysis of brown adipose tissue revealed an impaired morphology in both embryonic and adult p53-null mice. Thus, depending on the specific adipogenic differentiation program, p53 may exert a positive or a negative effect. This cell type dependent regulation reflects an additional modality of p53 in maintaining a homeostatic state, not only in the cell, but also in the organism at large.
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