IFN‐γ regulation of vacuolar pH, cathepsin D processing and autophagy in mammary epithelial cells

Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60614-3394
Journal of Cellular Biochemistry (Impact Factor: 3.37). 09/2008; 105(1):208 - 218. DOI: 10.1002/jcb.21814

ABSTRACT In this study we examined the ability of interferon-γ (IFN-γ) to regulate mammary epithelial cell growth and gene expression, with particular emphasis on two genes: Maspin (a member of serine protease inhibitor superfamily), and the lysosomal aspartyl endopeptidase cathepsin D (CatD). The protein products of these genes are critically involved in regulation of multitude of biological functions in different stages of mammary tissue development and remodeling. In addition, the expression of Maspin is down-regulated in primary breast cancer and is lost in metastatic disease, while CatD is excessively produced and aberrantly secreted by breast cancer cells. We report that IFN-γ receptors are expressed in mammary epithelial cells, and receptor engagement by IFN-γ transduces the IFN-γ signal via Stat-1 resulting in decreased vacuolar pH. This change in vacuolar pH alters CatD protein processing and secretion concurrent with increased Maspin secretion. In addition, IFN-γ exerts a suppressive effect on cell growth and proliferation, and induces morphological changes in mammary epithelial cells. Our studies also reveal that breast cancer cells, which are devoid of Maspin, are refractory to IFN-γ with respect to changes in vacuolar pH and CatD. However, Maspin transfection of breast cancer cells partially sensitizes the cells to IFN-γ's effect, thus providing new therapeutic implications. J. Cell. Biochem. 105: 208–218, 2008. © 2008 Wiley-Liss, Inc.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: To obtain a new expression for the communication channel capacity, the consideration is given to the space of signals that has orthogonal basis functions with alternating weight. Procedures for the determination of this weight are set forth. The complete system of orthogonal functions has been found from the obtained finite-dimensional basis.
    Microwave and Telecommunication Technology, 2003. CriMiCo 2003. 13th International Crimean Conference; 10/2003
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Proteomic studies in the mammary gland of control lactating and weaned rats have shown that there is an increased pattern of nitrated proteins during weaning when compared with controls. Here we report the novel finding that cathepsin D is nitrated during weaning. The expression and protein levels of this enzyme are increased after 8 h of litter removal and this up-regulation declines 5 days after weaning. However, there is a marked delay in cathepsin D activity since it does not increase until 2 days post-weaning and remains high thereafter. In order to find out whether nitration of cathepsin D regulates its activity, iNOS (inducible nitric oxide synthase)(-/-) mice were used. The expression and protein levels of this enzyme were similar to WT (wild-type) animals, but the proteolytic activity was significantly reduced during weaning in knockout compared to WT mice. in vitro treatment of recombinant human cathepsin D or lactating mammary gland homogenates with relatively low concentrations of peroxynitrite enhances the nitration as well as specific activity of this enzyme. Using MS, it has been shown that the residue Tyr168 was nitrated. All of these results show that protein nitration during weaning might be a signalling pathway involved in mammary gland remodelling.
    Biochemical Journal 02/2009; 419(2):279-88. DOI:10.1042/BJ20081746 · 4.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Viral proteins are usually processed by the 'classical' major histocompatibility complex (MHC) class I presentation pathway. Here we showed that although macrophages infected with herpes simplex virus type 1 (HSV-1) initially stimulated CD8(+) T cells by this pathway, a second pathway involving a vacuolar compartment was triggered later during infection. Morphological and functional analyses indicated that distinct forms of autophagy facilitated the presentation of HSV-1 antigens on MHC class I molecules. One form of autophagy involved a previously unknown type of autophagosome that originated from the nuclear envelope. Whereas interferon-gamma stimulated classical MHC class I presentation, fever-like hyperthermia and the pyrogenic cytokine interleukin 1beta activated autophagy and the vacuolar processing of viral peptides. Viral peptides in autophagosomes were further processed by the proteasome, which suggests a complex interaction between the vacuolar and MHC class I presentation pathways.
    Nature Immunology 04/2009; 10(5):480-7. DOI:10.1038/ni.1720 · 24.97 Impact Factor
Show more