Now showing 1 - 2 of 2
  • Publication
    HGF induces epithelial-to-mesenchymal transition by modulating the mammalian Hippo/MST2 and ISG15 pathways
    Epithelial to mesenchymal transition (EMT) is a fundamental cell differentiation/dedifferentiation process which is associated with dramatic morphological changes. Formerly polarized and immobile epithelial cells which form cell junctions and cobblestone-like cell sheets undergo a transition into highly motile, elongated, mesenchymal cells lacking cell-to-cell adhesions. To explore how the proteome is affected during EMT we profiled protein expression and tracked cell biological markers in Madin-Darby kidney epithelial cells undergoing hepatocyte growth factor (HGF) induced EMT. We were able to identify and quantify over 4000 proteins by mass spectrometry. Enrichment analysis of this revealed that expression of proteins associated with the ubiquitination machinery was induced, whereas expression of proteins regulating apoptotic pathways was suppressed. We show that both the mammalian Hippo/MST2 and the ISG15 pathways are regulated at the protein level by ubiquitin ligases. Inhibition of the Hippo pathway by overexpression of either ITCH or A-Raf promotes HGF-induced EMT. Conversely, ISG15 overexpression is sufficient to induce cell scattering and an elongated morphology without external stimuli. Thus, we demonstrate for the first time that the Hippo/MST2 and ISG15 pathways are regulated during growth-factor induced EMT.
      1018Scopus© Citations 64
  • Publication
    Changes in the endometrial transcriptome during the bovine estrous cycle: effect of low circulating progesterone and consequences for conceptus elongation
    In cattle, elevated concentrations of circulating progesterone (P4) in the immediate post-conception period have been associated with an advancement of conceptus elongation, an associated increase in interferon-tau production and higher pregnancy rates. Low P4 has been implicated as a causative factor in the low pregnancy rates observed in dairy cows. The aims of this study were (1) to describe the changes that occur in the bovine endometrial transcriptome during the estrous cycle, (2) to determine how elevated P4 affects the temporal pattern of gene expression in the endometrium of cyclic heifers, (3) to determine if the expression of these genes is altered in heifers with low P4 and (4) to determine the consequences of low P4 for conceptus development following embryo transfer. The main findings were that 1) relatively few differences occurred in endometrial gene expression during the early luteal phase of the estrous cycle under normal concentrations of P4 (Day 5 versus Day 7) but comparison of endometria from more distant stages of the luteal phase (Day 7 versus Day 13) revealed large transcriptional changes; 2) exogenous supplementation of P4, leading to elevated concentrations from Day 3 to Day 8, considerably altered the expression of a large number of genes at all stages of the luteal phase; 3) induction of low circulating P4 altered the normal temporal changes that occured in the expression of these genes, mainly by delaying their expression; 4) this delay in gene expression was, in part, due to delayed down regulation of the PGR from the LE and GE, and 5) the altered endometrial gene expression induced by low P4 was associated with a reduced capacity of the uterus to support conceptus development after embryo transfer on Day 7. In conclusion, the present study provides clear evidence for a temporal change in the transcriptomic signature of the bovine endometrium which is sensitive to the concentrations of circulating P4 in the first few days after estrus and which can, under conditions of low progesterone, lead to an suboptimal uterine environment and a reduced ability to support conceptus elongation.
      498Scopus© Citations 232